drug discovery 究 pipeline - gibhenglish.gibh.cas.cn/pd/201402/p020140219599252758828.pdf ·...
TRANSCRIPT
Mission of the Drug Discovery Pipeline
(DDP)
2
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Stem Cell Biology
& Regenerative
Medicine
(iSCBRM)
Chemical Biology
(iCB)
Infection &
Immunity
(I3)
Drug Discovery
Pipeline
(DDP)
GIB
H A
cad
em
ic I
nsti
tute
s
Drug
Candidates (3)
Clinical
Trials 60+
Staff (0)
DDP Mission: Act as a translational center for GIBH by providing:
• Expertise
• Platform/core technologies,
• Integrated project teams
• Funding to develop new drugs
New department
created in 2009
GIBH consists of 3 scientific institutes and 1 translational center
Milestones for the DDP
3
(1) Formation and integration of project teams to enable the advancement of
drugs
(2) Centralization of core technologies to support drug development
(3) Development of a sustainable pipeline of projects with novel intellectual
property
(4) Establishment of key international partnership for the co-development of
drugs
(5) Recruitment of international experts with discovery experience to enable
effective drug discovery science at GIBH
(6) Provision of technical services and internal expertise to local universities
and companies in Southern China
(7) Licensing of intellectual property and drugs matured in the DDP to
pharmaceutical companies in Guangzhou for advanced clinical
development.
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DDP continues to approve upon seven important milestones
Formation of Project Teams
4
Project
Chemistry Leader
Team Members
Molecule design
Synthesis
Purity
Crystallography
Scale-up
Formulations
Team Members
Protein
Screening
Enzymology
Biomarker validation
Animal models
PK/ADME
Safety
Biology Leader
High Through-Put Screening Capable of screening thousands of compounds per week in various enzyme and cell based assays at a low price
Structural Biology Allows us to optimize lead compounds using computer aided design as well as virtual screening
Pharmacokinetics/Pharmacodynamics/ADME Defines the PK and safety properties of our lead compounds
Biomarkers and Epigenetics Validates the efficacy and safety of our drugs in pre-clinical models
Medicinal Chemistry Design, synthesis and formulation of new drugs with IP
Bio-Therapeutics The use of proteins as active agents to treat diseases
Integrated Project Teams Centralized Core Technologies
Project teams provide the critical mass and expertise needed to advance drugs in the pipeline
i. “Project” vs. “PI” centric structure
ii. Core labs primarily support projects
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Research Project Teams (RPT)
5
Lead
Development
EE HI LD CS IND Phase 1
Candidate
First in
Humans Idea
Department Head
(DH)
Research Project
Leader (RPL)
Research Project Team
RPTs are responsible for projects from early exploration to first in humans
The Research Project Leader (RPL) leads the project team and is empowered to declare milestone
decisions for all stage gates of the program
Department Head(s) (DH) is responsible for selecting RPLs and for configuring and providing
resources for research project teams based on evolving needs of the program
Research Project Teams are the core of the DDP
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Centralization and Expansion of Core
Technology Labs 6
Chief Technology Officer
(Micky Tortorella) Chemistry (Ding Ke): 13 RA
Director of
Chemical
Biology
Biology (Team Leaders): 8 RA
HTS (Zhengchao Tu): 6 RA
PK/PD/ADME (Xiaorong Liu): 7 RA
Structure (J.Liu & R.Jauch): 6 RA
Epigenetics (A. Strunnikov): 5 RA
Bio-Therapeutics (D. Yu): 4 RA
Analytical Chem (Y. Zhang): 6 RA
Administration
Business
Development:
3 FTE
Co
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ab
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DDP has 8 core labs that support and comprise project teams
Core technologies were
centralized and expanded
and now include 8 labs
Each lab is led by an
experienced scientist
Members from core labs
comprise project teams
High-Throughput Screening
7
The high-throughput screening (HTS) core lab has
been fully equipped:
Tecan liquid handling workstation
Envision multiple plate reader
Echo520 ultrasound liquid transfer system
Genpix400B chip scanner
The HTS Center has the capacity to perform more
than ten-thousand drug screening reactions per day
Tecan Envision Echo Genpix
High-throughput screening center has been established at GIBH
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Drug Screening Assays
8 HTS lab now offers >100 different screening assays against various targets
Drug Target Cmpd (hits)
Protein kinases ABL 683 (214)
ABL(T315I) 96(78)
ABL(E255K) 263(88)
ABl(G250E) 259(85)
Abl(Y253F) 258(79)
ABl(Q252H) 258(84)
ABl(H396P) 258(83)
ABl(M351T) 258(82)
ALK 213 (25)
Kit (GIST) 63 (48)
Her2 69 (43)
AKT1 200 (38)
AKT2 8 (6)
AKT3 8 (7)
EGFR 361(165)
EGFR (T790M) 123(106)
EGFR(L858R) 155(129)
EGFR(L861Q) 117(108)
EGFR(T790M&L868R) 177(123)
AuroraA 24(3)
AuroraB 24(3)
DDR1 112(91)
DDR2 70(26)
Met 17(0)
Proteases DPP4 28(28)
DPP8 35(2)
DPP9 35(3)
Cathepsin D 36(9)
Cathepsin E 36(20)
BACE-1 62(14)
PMII 125(99)
Pepsinogen C 11(1)
Pensinogen A 9(7)
ADAMTS13 227(20)
HIV-1 Protease 11 (3)
Drug Target Cmpd (hits)
HDACs
HDAC1 10(4)
HDAC2 17(11)
HDAC3 256(33)
HDAC4 10(5)
HDAC5 17(5)
HDAC6 17(15)
HDAC7 10(2)
HDAC8 122(116)
HDAC9 17(14)
HDAC10 17(15)
HDAC11 10(1)
Anti-inflammatory
COX-1 75 (32)
COX-2 75(62)
PGE2 75(48)
TXB1 75(32)
TNFa 156(6)
IL1b 130(16)
Anti-Influenza virus
NA-S 80 (41)
NA-R 80 (35)
M2 126 (67)
NP 242 (45)
CPE assay 6272(231)
Plaque Reduction Assay 45 (45)
CYP450 Assay
CYT450
CYP2C9 21(20)
CYP3A4 21(17)
CYP2D6 21(15)
CYP1A2 21(5)
CYP2C19 21(18)
Drug Target Cmpd (hits)
Cancer cell toxicity A549 3162(146)
BGC823 372(44)
DU145 385(63)
Molt-4 372(65)
K562 62(47)
Hela 372(54)
HT1080 572(54)
MCF-7 672(47)
U937 372(61)
Othe cell-based assay
SNX10 3176(262)
Boris antagonist 3200(19)
GPCRs
BMP4 antagonist 2540(179)
BMP4 agonist 2540(3)
CCKB agonist 975(2)
OPRM1 antagonist 975(0)
Assay formats include
96, 384, and 1536 well
plates and FRET,
polarization, alpha screen,
cell, luminescence etc.
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Creation of a Chemical Library
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1. GIBH internal compounds
- All compounds submitted for screening are now ID, categorized, plated and deposited
in a central library
-These compounds are the most valuable
2. Purchased Compounds
- Structurally diverse compounds selected
- Include FDA approved drugs and pharmacologically active compounds
- Obey the rule of 5 including logP (<6), MW(300-700), no reactive groups, good
solubility etc.
GIBH library contains ~28K compounds and include:
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Footnote: New
CCKBR agonists
identified from
the library
Novel 3D surface
Carbene chemistry
Compound Microarrays
10
Universal Immobilization of Small Molecules
Surface plasmon resonance imaging for rapid screening of targets
Drug Protein Conc. (nM) KD (M)
(Avg)
IC50
PO1 PMII 50 &100 5.08e-8 1.2e-8
PO2 PMII 50 &100 7.46e-8 0.4e-8
~1500 GIBH compounds successfully
immobilized and screened on chips
Goal is to immobilize 5000 compounds
5000 spots per chip
2 plasmepsin inhibitors successfully bound to their target PMII protein and Kd values were similar to reported IC50 values from enzyme assay
Collaboration with Plexera to develop chemical microarrays for easy screening
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PK/PD/ADME Laboratory
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Analysis Compounds Tested
Pharmacokinetics 260
Protein binding 85
Metabolic stability 120
Drug-drug interaction 91
Glucose tolerance 4
Hepatocyte (toxicity) 8
Caco-2 21
Blood-brain penetration 7
Acute toxicity 9
Zebra fish (toxicity) 39
Core Competencies Productivity
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Footnote: PK
determinations
obtained early in
the testing funnel
Understanding the PK/PD relationship of our lead molecules
New In Vivo Pharmacology
Services 12
(4) Rat adjuvant arthritis
model
(1) Rat air pouch model
of inflammation (2) Rat acute carrageenan
induced edema model
(3) Hyperalgesia pain
model
New in vivo pharmacology services
offered in 2013
1. Acute rodent toxicity testing
2. Developed several new disease
animal models for screening anti-
inflammatory based drugs
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Services provided increase the survivability of our lead drug candidates
Highlight: These
animal models of
inflammation
enabled the
nomination of drug
candidate GIBH-
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Model Drugs Tested
Air pouch single dose 36
Air pouch ED50 30
Rat acute edema 24
Rat hyperalgesia 24
Rat arthritis 5
In Vivo Cancer Models
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Tumor Type Target # Drugs Tested
K562
(blood)
Bcr/Abl 12
Ba/F3-T315I
(blood)
Bcr/Abl(T315I) 11
A549
(lung)
EGFR(WT) 9
H1975
(lung)
EGFR(T790M/L
858R)
9
HT29
(colon)
bRAF(V600E) 7
HCT116
(colon)
bRAF(WT) 7
Rodent xeno/allograft models for determining efficacy of lead cancer drugs at GIBH
Normal Tumor Treatment
Xenograft Model:
Vehicle 5mg/Kg 20mg/kg
Allograft Model:
Highlight: These
animal models of
cancer enabled
the nomination of
drug candidate
D824
In vivo cancer model's lab is dedicated to
determining the efficacy of lead compounds
targeting blood, lung and colon cancers
Medicinal Chemistry Group
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Chemical Biology
~47 Chemists
DDP
16 Chemists
10
DDP has a “project dedicated” core of medicinal
chemists
DDP works closely with members in Chemical Biology
Several senior chemists in Chemical Biology have
projects with the DDP
This model of collaboration maximizes (doubles) the
chemistry resources for research project teams
Target Disease ~ Compounds
Made
Cancer 320
Arthritis 60
Alzheimer’s 230
Diabetes 330
Flu 120
Malaria 210
Pain 100
Productivity
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The group has made several thousand new proprietary chemical entities
Center for Analytical and Formulation
Chemistry 15
I. The Center has a brand-new lab site, which was completed in 2013 and
designed to form a modern analytical laboratory
II. The Center provides drug formulation, chemical analysis and quality
control for all molecules made at GIBH
III. The Center has been equipped with key instruments including a heavy
pressure tablet machine, zetasizer, HPLC, LC-MS, GC- MS, LC-
MS/MS, element analyzer, Prep HPLC, NMR(400MHz),
NMR(500MHz), IR spectrometer, UV spectrometer, X-ray diffraction,
Polari meter, melting point machine and PH meter
IV.Certification of ISO 17025 is expected in March of 2014
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Center has the capability to provide chemical analysis and solid dosage formulation
Analytical Center Core Competencies
and Productivity 16
Instrument
Name
Total
Usage
(Times)
Chromatographic Lab
HPLC(Analysis) 572
HPLC(Chiral Analysis) 754
HPLC(Preparation) 345
LC-MS 396
Spectrometer Room
Ultraviolet-Visible
Spectrophotometer 0
Infrared spectrometer 93
Automatic control
temperature type
polarimeter
143
Chemical Analysis
Lab
Acidimeter 0
X-6 series digital
melting point tester 51
Electronic Balance 76
Total 2430
Center has conducted over 2000 analyses
1) Chemical Analysis Core mainly
performs analysis on organic
compounds and is equipped with
HPLC, LC-MS, GC-MS, LC-MS/MS,
element analyzer, Prep HPLC, NMR
(400MHz), NMR (500MHz), IR
spectrometer, UV spectrometer, and
X-ray diffraction
2) Formulation Core provides services
related to chemical formulation and
contains key equipment including a
high-performance coating machine,
centrifugal granulation coating
machine, freeze dryer, zetasizer,
heavy pressure tablet machine and
high pressure homogenizer
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Structural Biology
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3. Plasmepsin Project: PMII and PMIV expression,
purification and co-crystal screening of lead
compounds.
4. Cox-2 Project: predicting the binding mode and
interactions of lead compounds to drive potency.
1. New Super Computer Platform with a total peak
performance of up to 1.2T flops, plus 192GB
memory and 10TB storage, which provides
enormous support for high-throughput virtual
screening and biological macromolecule modeling.
2. CCKBR Agonist: CCKBR agonist design by CADD
(computer aided drug design), ~150 hit compounds
were selected for activity testing. CCKBR homology
model building and in silico screening of internal compound
database (~30,000), 124 hits were ID for testing.
Team supports target validation, lead generation and lead optimization for discovery projects
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Impact Highlights
Footnote:
Invested 3M
rmb into
platform
Bio Therapeutics & Recombineering Lab
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(2) Therapeutic protein development
The lab is developing a recombinant protein of
ADAMTS-13 for the treatment of thrombotic
thrombocytopenic purpura (TTP)
ADAMTS-13 cleaves and disaggregates vWF
in the blood preventing blood clots
(1) A core for gene knockout and transgenic mice
Lab uses “recombineering” technology for construction
of DNA targeting vectors
KO mice are used for target validation, toxicity evaluation
and disease models
Gene Knockout and Transgenic
Construction 19
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Gene knockout targeting vector construction
Mouse ES clone generation
Develop knockout mice
Gene
Name
KO
Type
Targeting
Vector
ES cell
Clone
Blastocyst
Injection Chimeras
Het and
Hom
Jhdm1a KO Completed Completed Completed Completed Processing
Jhdm1b KO Completed Completed Completed Completed Processing
Snx17 KO Completed Completed Completed Completed Processing
NeuroD1 iKO Completed Completed Completed Processing
Nras KO Completed Processing
Setdb1 CKO Completed Processing
Snx21 CKO Completed Processing
Pcgf5 CKO Completed Processing
Cckbr
KO Completed Processing
Core Competencies
Productivity
KO, Conventional; iKO, Inducible; cKO, Conditional
Dr. Daiguan Yu, head of Bio-therapeutics Lab is an inventor of “recombineering” technology
Project Progress for ADAMTS13
20 Recombinant ADAMTS13 and its stealth
versions constructed and cloned
rADAMTS13 protein expressed
folded and purified ~120 kDa
rADAMTS13 is active in a peptide
assay of FRETS-WF73
rADAMTS13 is proteolyticly
active against native human vWF factor
Studying PK/PD relationship in mouse model of TTP
Initiating manufacturing of GMP grade protein
Control ADAMTS13
176 kDa
140 kDa
vWF Control Cleaved vWF
5 ng ADAMTS13-MDTCS
4 ng ADAMTS13-MDTCS
3 ng ADAMTS13-MDTCS
2 ng ADAMTS13-MDTCS
No ADAMTS13-MDTCS
Invisible to auto antibodies
Peptide spanning the
cleavage site in vWF
1
2
3
4
5 rADAMTS13 proteins degrade
vWF multimers in plasma of TTP patients
GIBH
A single proteinase molecule can inactivate or activate thousands of target molecules
1 .patient 1
2. patient 1 + rADAMTS13-MDTCS
3 .patient 2
4. patient 2 +rADAMTS13-MDTCS
5. normal1
6. normal1 +rADAMTS13-MDTCS
1 2 3 4 5 6
Molecular Epigenetics Laboratory
(MEL) 21
Core Competencies
- Cell-based screening assays
- Protein-protein interaction assays
- Chromosome and chromatin analyses
using NGS and ChIP-seq
Ongoing Projects
1. Cancer biomarkers: mAbs being generated to 50 identified cancer-testis
(CT) specific genes
2. Anticancer drug discovery: Developing inhibitors of BORIS, an 11-zinc-
finger epigenetic reprogramming factor, specific for testis and turned on in
many cancers – Hits identified from internal compound library
3. Novel cancer pathways: Using epigenomics in mapping chromosomal
breakpoints associated with dysfunction of specific pathways of chromosome
integrity and cancer
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New biomarkers lab created in the DDP
MEL to Study Cancer and Biomarkers
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An epigenetic approach to find new cancer biomarkers and therapeutics:
- Readers of epigenetic marks such as global transcription
regulators
- Targeting proteins only expressed in testis and cancer
Potent biomarkers Ideal anticancer targets for chemical inhibitors
and cancer immunotherapy
No expression in normal somatic tissues
• Current CT database includes 268 gene families
• Using human testis CAGE, MEL has identified hundreds more
• MEL is currently working on two cancer targets Boris and meiotic cohesin complex
CT genes = genes expressed
specifically in cancer and testes
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CT genes may be safe targets for drug intervention
Genome Regulation Laboratory
(GRL) 23
Core Competencies
- Structural Biochemistry
- Computational Genomics
- Genome Regulation
- Cellular Reprogramming
Research Program
1. Decoding/manipulating genome regulation: Elucidating how transcription
factors combinations selectively target enhancer DNA and the enhancer code that
determines cell fates and how transcription factors “ read” this code
Drug Discovery Projects
2. SOX18: Identifying novel small molecule blockers of SOX18 as possible anti-
cancer drugs
3. Disease modeling & cell therapies: Producing synthetic factors for cellular
reprogramming (i.e. small molecules and proteins)
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Decoding and Manipulating Genome Regulation for Cell Therapies and Drug Development
Product Portfolio 2011
24
Early Exploration
Hit Identification
Lead Optimization
Drug Candidate Selection
Out-License
Clinical Testing
Discovery Pre-Clinical Development Clinical
Development
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Cartilage
Re-growth
ADAMTS-13
3rd Gen. COX-2
inhibitors
Plasmepsin
inhibitors
Anti-OA siRNAs
2nd Gen. Kinase
inhibitors
Oral Anti-AD drug
The beginning of a sustainable pipeline of projects
Product Portfolio 2014
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Early Exploration
Hit Identification
Lead Optimization
Drug Candidate Selection
Out-License
Clinical Testing
Plasmepsin
inhibitors
Anti-OA siRNAs
ADAMTS-13
CCKBR agonist
DDR1 inhibitor
EGFR inhibitor
Cartilage
Re-growth
BCL11b
BORIS
SOX18
Discovery Pre-Clinical Development Clinical
Development
2nd Gen. Kinase Inhibitor
GZ824
Guangzhou Shunjian Pharma
Oral Anti-AD drug
GIBH130
SCCIP
3rd Gen. COX-2 Inh
Movement of projects forward:
3 projects advanced to CS
2 CS projects were out-licensed
2 projects moved to LD
3 projects entered HI
Significant addition and advancement of projects forward in the Pipeline
Inhibitors of Neural Inflammation as New Agents
for Alzheimer’s Treatment
O
OH
O
NH2NH2/ethanol
N NH
O
Br2/CH3COOH
80-100 ¡æ, 2h N NH
O
POBr3/CH3CN
N N
Br
CuCN/ dry DMF
N N
CNcon. HCl
90¡æ, 4h
N N
COOH
HN N
N
N
EDC/HOBt/TEA/DCM N N
N
O
N
N
N
400.0g 374g
450g(300g)
24g(3g) 25g(15g)
yield: 93.9%
yield: 40.5%yield: 92.1%
yield: 91.6%
yield: 68%,over night
yield: 63.2%
360g
100¡æ, 4h
140¡æ, 5hrefluxed, 3h
GIBH 130
MW = 360
cLogP 0.59
LogP 3.1
Project Leaders: Wenhui Hu, GIBH and Donghai Wu, GIBH
Neuro-inflammation mediated by microglia cells in the brain is responsible for progression of AD
Potency
Microglia Activation IC50 = 0.002 uM
Toxicity
hERG IC50 = >100 uM
Pharmacokinetics
BA 75 %F
Tmax 0.6 hr
Cmax 33,387 ug/L
Vd
T1/2 hr 4.3 hr
BBB
Brain AUC 17,706 ng/ml
CSF AUC 889 ng/ml
In Vivo Efficacy in Rodent Models Aβ-model of AD >90% reduction at 0.25mg/kg
APP/PS1 transgenic mouse >80% reduction at 0.25mg/kg
model of AD
Ischemia stroke model >50% reduction at 1.0 mg/kg
Collagen induced arthritis >70% reduction at 0.5mg/kg
In Vivo Safety
Acute Rat MTD > 600 mg/kg
Compound Profile In Vivo Efficacy
Group Dose
(mg/kg) Latency
(s)
Control 173.74±94.66
Model 78.78±117.73#
Donepezil 1.3 218.12±110.36**
Memantine 2.6 179.20±113.03*
GIBH-130 0.25 186.75±81.70*
0.028 238.25±75.87**
0.0031 141.93±87.41
APP/PS1 Transgenic Mice
Memory Improvement
Progress:
Lead Optimization to Clinical Candidate in 2012
Licensed candidate to SCCIP in 2013 where GIBH
maintains 50% ownership of the IP
SCCIP will pay 12M rmb to complete the IND package and
file with sFDA and USA FDA
SCCIP is responsible for clinical development costs
Next milestone is IND acceptance in 2014
>250 analogs synthesized >1000 grams of GMP grade
Excellent CNS
penetration
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CF3
N
NH
O
N
N
HN
N 2CH3SO3H
New Bcr-Abl Inhibitors for the Treatment of
Chronic Myeloid Leukemia (CML) Resistance Project Leader: Ke Ding, GIBH
Bcr-Abl kinase mutation is primarily responsible for CML resistance against Imatinib
GZD824
MW = 533
Potency
IC50 values nM
Bcr-Abl WT 0.34
Bcr-Abl T315I 0.68
K562 CML cells 0.2
Ku812 CML cells 0.13
SUP-B15 ALL cells 2.5
Kd values:
nonphosphorylated
Bcr-AblWT 0.32
Bcr-AblT315I 0.71
phosphorylated
Bcr-AblWT 0.34
Bcr-AblT315I 3.20
Pharmacokinetics (oral)
BA 48.7%F
Tmax 4.0 hr
Cmax 390 ug/L
T1/2 hr 10.6 hr
In Vivo Efficacy in mice xenograft models
K562, Ku812, Bcr-Abl WT, Bcr-Abl T315I,
Bcr-Abl E255K, Bcr-Abl G250E and Bcr-Abl F317L
Compound Profile In Vivo Efficacy >400 analogs synthesized
>1000 grams GMP grade Vehicle
1 100 mg/kg
10a 2 mg/kg
10a 5 mg/kg
10a 10 mg/kg
10a 20 mg/kg
10a 1 mg/kg
Day 0 Day 7
Vehicle
1 100 mg/kg
10a 2 mg/kg
10a 5 mg/kg
10a 10 mg/kg
10a 20 mg/kg
10a 1 mg/kg
Day 0 Day 7
Progress:
Lead Optimization to Clinical Candidate in 2012
Licensed to Guangzhou Shunjian Pharmaceutical, in 2013 who will
cover the costs for IND and beyond and provide GIBH with up to
100M RMB in milestone based payments
Next milestone is IND acceptance in 2014
Efficacious
dose is between
1 to 10 mg/kg in
a model of
leukemia
Luciferase
detection (blue
intensity) as a
measure
of leukemia
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Renal Sparing COX-2 Inhibitors for the Treatment of
Inflammation and Acute Pain Project Leaders: Yanmei Zhang, GIBH and John Talley, USA
COX-2 is responsible for the production of prostaglandins at sites of inflammation
GIBH 1014
MW = 340
S-isomer
Potency
COX-2 IC50 = 0.014 uM
Selectivity
COX-1 IC50 = >100 uM
Pharmacokinetics
BA 107 %F
Tmax 0.47 hr
Cmax 35,300 ug/L
Vd 0.53 L/kg
T1/2 hr 5.2 hr
In Vivo Efficacy in Rat Models
Air pouch inflammation ED50 = 0.34 mg/kg
PGE2 Levels
Thermal hyperalgesia ED50 = 2.2 mg/kg
Paw edema ED50 = 3.0 mg/kg
Adjuvant Arthritis ED50 = 0.42 mg/kg
O
Br CO2H
CF3
CD3
Progress: 1. Hit ID to Lead Optimization in 2012 and 2. LO to Clinical Candidate selection in 2014
Compound Profile In Vivo Efficacy
Rat Thermal
Hyperalgesia
Adjuvant Arthritis Model
Low volume of
distribution may
explain selective
localization
>250 analogs synthesized
GMP manufacturing initiated
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EC50 = 0.42 mg/kg 16
14
12
10
8
6
4
2
0 Veh Ind 0.01 0.1 0.3 1 3 10
GIBH1014 mg/kg
Art
hritis S
core
GIBH1014
(mg/kg)
PWTL (%)
Pain
Vehicle 100
1 64.5±7.8
3 41.3±5.9
10 15.1±4.8
30 4.8±2.0
Compound Profile In Vivo Efficacy
Plasmepsin Inhibitors as Novel Anti-malarial Agents
GIBH 117
MW = 393
cLogP = 3.6
achiral
Progress: Hit Id to Lead Optimization in 2012, next milestone is clinical candidate selection in 2014
Project Leaders: Xiaoping Chen, GIBH and Marvin Meyers, SLU
Plasmepsins are aspartyl proteases important for malaria survival
>300 analogs synthesized
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Dose-dependent inhibtion of compound
GIBH117 in the P. chabaudi ASCQ-infected
murine four-day suppressive test.
Potency IC50 (µM)
Pf 3D7 72h 0.463
Pf Dd2 72h 0.480
Pf 3D7 48h 0.751
Plasemepisn II 0.004
Plasemepisn IV 0.015
Selectivity IC50 (µM)
BACE 12
CatD >10
CatE 1.2
In vitro safety IC50 (µM)
CYP1A2 >10
CYP2C19 5.48
CYP2D6 >10
CYP3A4 0.449
Pharmacokinetics
MLM t1/2 (min) 81
RLM t1/2 (min) 61
HLM t1/2 (min) 29
hPPB (%) 98.5
Rat PK t1/2 (h) 2.9
Rat PK oral bioavailability (%F) 16
Red blood cell ,
infection assays
Highlight: Project was
awarded the
NIHR01/NSFC USA-
Chinese collaborative
research grant in 2014
~6M¥
1000
100
10
1
0.1
0.0
01
0.0
1
0.1
1
10
Lo
g p
f3D
7 C
ell
IC
50 (m
M)
Log PMII Enzyme IC50 (mM)
Correlation between
inhibition of PMII & red
blood cell infection
by malaria
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Therapeutic siRNAs for Treating Osteoarthritis Project Leaders: Biliang Zhang and Micky Tortorella, GIBH
Genes R001 and R002 mediate cartilage breakdown and inflammation, respectively in OA
Compound R001 and R002 consists of ~ 20 base pairs of dsRNA
R001 is selective for gene ADAMTS-5 and R002 is specific for gene R002
The 3’ends of both molecules are conjugated to a cholesterol analog for
enhanced cell permeability
1.2
1.0
0.8
0.6
0.4
0.2
0
Rela
tive
Ex
pre
ss
ion
R001 R002
siRNA
No Target
Synovial Fibroblasts In vitro both siRNAs permeate
synovial fibroblasts (major cell type
of the joints)
Targeted genes effectively blocked
by synthetically designed siRNAs
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2
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Compound
Potency
Delivery and Retention in the Joints
ECM (reservoir for agent)
Intra articular injection
(IA)
Cartilage
A proprietary formulation using polyarginine peptides
was developed
Retention in the cartilage of cy3red-labeled siRNA is
observed even after 2 weeks following IA injection
Intense staining seen both in the ECM and cells
Once a quarter dosing a FDA requirement may be
achievable with such a vehicle
Chondrocytes (target)
R001
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>100 molecules synthesized
GIBH-R001/2
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Inflammatory (CIOA)
osteoarthritis model • 6 week model
• Severe Fibrosis
• Cartilage erosion
Intra-articular
treatment with siR001
• Dosed 2x a week
• 10 nmols/knee (100ul)
Severe fibrillation down to the layer immediately below the superficial layer
Low grade fibrillation
Severe fibrosis and loss of cartilage in meniscus
No structural changes
Healthy cartilageCalcified cartilage
Disease siR001-2
siR001-2 effectively blocked disease
progression
Blocked all components of the disease - Fibrillation
- Fibrosis
- Cartilage erosion
Unprecedented efficacy for a DMOAD
Therapeutic efficacy also demonstrated
Next step is optimizing the formulation of
siR001-2
Candidate Selection planned for early 2014
Histology of knee joints
Therapeutic siRNAs for Treating Osteoarthritis
In Vivo (Histological) Validation
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siRNA Team Members
Bio-Surgery approach for treating OA
New Project Entries
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Target Function Drug Class Therapeutic
Indication
Project Leaders
Cholecystokinin B
Receptor (CCKBR)
Influences neuro-
transmission in the
brain, regulating
memory
Oral, small molecule
agonist
Dementia
Downs Syndrome
Alzheimer's
Jufang He
Yanmei Zhang
Discoidin domain
receptor family,
member 1 (DDR1)
Regulation of cell
growth, differentiation
and metabolism
Oral, small molecule,
tyrosine kinase inhibitor
Kidney Fibrosis
Lung Fibrosis
Lung Cancer
Ding Ke
Epidermal growth
factor receptor (EGFR)
with drug resistant
mutations
Overexpression has
been associated with a
number of cancers
Oral, small molecule,
tyrosine kinase inhibitor
to mutant forms of
enzyme
Lung Cancer
Liver Cancer
Colon Cancer
Breast Cancer
Reversible inhibitor
Ding Ke
Irreversible Inhibitor
Zhang Jiancun
Yanmei Zhang
Brother of Regulator of
Imprinted Sites
(BORIS)
Testis specific, 11-zinc
finger factor involved in
gene regulation
Oral, small molecule
blockers
Various cancers that
express BORIS
Alex Strunnikov
B-cell
lymphoma/leukemia
11B (BCL11B)
C2H2-type zinc finger
protein that maybe
linked to leukemia's
Oral small molecule
modulators
Leukemia's
Li Ping
SOX18
Transcription factor
involved in the
determination of cell
fate
Oral, small molecule
blockers
Cancer Ralf Jauch
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Newly endorsed or projects under consideration
Footnote:
Cancer and
inflammation are
becoming the
major focus at
GIBH
Project Evaluation and Ranking
33
Projects are evaluated and ranked
based on:
1. Meeting key principles of drug
discovery including demonstration
of (I) drug exposure at the target
site of action; (II) drug binding to
the pharmacological target and;
(III) expression of pharmacology
2. Timely advancement from one
stage gate to the next
Projects that meet key criteria are
supported with significant resources
and are deemed Tier I.
Exp
osu
re
Co
nfi
den
ce
Pharmacology Confidence
None or Partial Principles
Binding to target but no data to
show relevant downstream
pharmacology effect; exposure
only in plasma, not at target site
(eg CNS); PKPD not well
established
Serious concerns that
mechanism can be tested &
clinical studies unlikely to be
definitive
Principles I and II
Target exposure and target binding
concur but no data to show relevant
downstream pharmacology effect or
data is not at site of action.
Risk in relying only on exposure
and binding; study design &
decision-making from clinical
endpoint needs to be crisp
Principles I,II,III
Target exposure shown and
concurs with target binding which
results in expression of relevant
downstream pharmacology affect at
site of action. PKPD well
established. Maximum confidence
in translation of drug exposure
and pharmacology & of testing
the mechanism
Principles II and III
Binding to target shown but
exposure only in plasma, not at
target site (eg local administration
to target); data showing relevant
downstream pharmacology effect.
Reasonable risk being carried
forward if confident that drug
reaches target in humans &
clinical endpoint relevant to site
of action
Hi, Hi
Lo, Lo
Risk Management with respect to ensuring project success
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Mo
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roje
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fall h
ere
Project Evaluation and Ranking
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Stage Gates Symbol DDP Average Times
Early exploration EE 6 months
Hit Identification HI 5 months
Lead Optimization LO 1-2 years
Candidate Selection CS 1-2 years
Clinical Testing CT NA
Out-License OL 1 year
Target Progress
Mutant
Bcr-Abl
kinase
2009: HI
2010: LO
2011: LO
2012: CS
2013: OL
Microglia macrophages
of the brain
2009: HI
2010: LO
2011: LO
2012: CS
2013: OL
COX-2
enzyme
2010: HI
2011: LO
2012: LO
2013: CS
Plasmepsins Aspartyl
proteases
2010: HI
2011: HI
2012: LO
2013: LO
Target Progress
ADAMTS-5 +
ADAM-17
2009: EE
2010: HI
2011: HI
2012: LO
2013: LO
ADAMTS-13 2010: EE
2011: HI
2012: LO
2013: LO
EGFR mutant
kinase
2012: HI
2013: LO
Cholecystokinin
B Receptor
(CCKBR)
2012: EE
2013: HI
Average time needed for projects to advance to the next stage gate
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Projects in the DDP have advanced at
timelines consistent with industry
averages published by various
pharmaceutical companies over the
years
Key International Collaborations
The Center for World Health & Medicine at Saint Louis University
Development of inhibitors of plasmepsin V as novel anti-malarial agents
Dr. John J. Talley, inventor of Celebrex and Bextra
Development of 3rd generation Cox-2 selective inhibitors for inflammation and pain
Professor Jufang He at Hong Kong Polytechnic University
Advancement of CCKBR agonists for the improvement of memory
Plexera Inc.
Development of compound micro array chips for repositioning of clinical candidate drugs
Professor Anne-Marie at Rush Medical Center
Understanding chondro- genesis and the biology of OA pain using engineered cells/mice
Shanghai Institute of Material Medica
Development of EGFR inhibitors for the treatment of cancers
Collaborations allow GIBH to share the risk and expenses associated with drug development
GIBH
35
Recruitment of international experts
36
Micky Tortorella is a former Senior Principal Investigator at Pfizer (2001-2009) with 15 years’ experience
in the pharmaceutical industry. Prior to working at Pfizer he had a successful tenure as a Research
Scientist at DuPont Pharmaceuticals (1993-2000). He is regarded as a key opinion leader in the United
States as well as internationally in drug discovery, osteoarthritis and metalloproteinase biology.
Dr. ZhengchaoTu obtained his Ph.D. from Northwest A&F University and Kunming Institute of Zoology,
Chinese Academy of Sciences in 1996. He did his post-doctoral research at Fudan University (1996-
1998). Before joining GIBH in 2010, he was a senior scientist and director in Reaction Biology Corp. USA,
where he focused on high throughput drug screening.
Dr. Ralf Jauch studied Biology in Jena (Germany) and Manchester (UK) before doing his PhD in a
molecular biology program from 2001-2005 at the Max-Planck-Institut für biophyskalische Chemie in
Göttingen, Germany. In 2006 he joined the Genome Institute of Singapore From 2008-2013 he continued
at the GIS as a research scientist. In 2013 he joined GIBH.
Dr. Alex Strunnikov received his Ph.D. from the Institute of Cytology, St. Petersburg, Russia, where he
cloned and characterized the SMC1 gene. Then,the United States, where he got a postdoctoral position at
the Carnegie Institution of Science, Department of Embryology. In 1996 Dr. Strunnikov was recruited by
NIH, where he stayed, at NICHD and then NIAID, up until 2011.
International team of scientists with overseas training
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Recruitment of international experts
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Dr. Daiguan Yu previously was a Research Fellow working at National Cancer Institute-Frederick,
Maryland where he invented “Recombineering”, an advanced gene engineering technology. From 2001 to
2009, he took a position in Lexicon Pharmaceuticals Inc. in Texas. He was then invited as Scientific
Specialist to Sanger Institute at Cambridge, UK from 2009 to 2010.
Dr. Yanmei Zhang got her Ph.D. from Technical University of Munich, Germany in 2004. Her work focused
on organic catalysis and methodology. Before joining GIBH, Dr. Zhang worked at the drug discovery center
of UCSD Cancer Center with Prof. Dennis Carson on the design and synthesis of AdSS inhibitors and the
formulation of active small molecules in liposome form.
Dr. Chris Zhang received a PhD in Immunity from the Sheffield Medical School followed by a postdoctoral
fellowship in the Department of Cardiovascular Research at Royal Hallamshire Hospital. He then joined
industry as a Senior Research Scientist at Molecular Devices, before joining GIBH in 2013. As a Principle
Investigator he is developing new applications across a number of instrument platforms using iPSCs.
Diversity allows the research teams to approach each project in a very unique way
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Provision of Services to Local
Universities 38
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As a means for stimulating scientific excellence in China, GIBH offers its drug development expertise and
platform technologies to universities and small companies in Guangdong province
GIBH offers services in compound screening, drug pharmacokinetics and analytical chemistry
High-throughput screening center
Company Name Service Provided
• South China Sea Institute of Oceanology, CAS. Guangzhou Anti-cancer cell based assays
• Kunming Institute of Botany, CAS. Kunming Anti-cancer and anti-flu screening
• China Pharmaceutical University. Nanjing Anti-cancer assay
• East China University of Science and Technology Shanghai Anti-cancer
• Sun Yat-Sen University. Guangzhou Anti-flu screening
• WuXi AppTec. Shanghai Anti-cancer assays
• Jinan University. Guangzhou Anti-Cancer and anti-flu screening
• The Hong Kong Polytechnic University. Honghong GPCR assays
• Minzu University of China. Beijing Anti-TB assay
Center of drug metabolism and pharmacokinetics
Company Name Service Provided
• Guizhou institute of biology Analysis of biological samples using LC/MS/MS
• Guangdong Lingnan Pharmaceutical Co., Ltd Analysis of biological samples using LC/MS/MS
• Guangzhou Hua Po Biotechnology Co.,Ltd Analysis of biological sample using LC/MS/MS
• High-tech Da An Health Industrial Investment Co.,Ltd
LC/MS/MS to screen for early genetic metabolic
markers for neonate
1
2
Intellectual Property
39
Publications 19 Papers
Intellectual Property 20 Patents
Research Grants 6 Grants
Technology Transfer 2 Licenses
• ACS Med. Chem. Lett. 2010, 1 (9), 454–459
• Current Medicinal Chemistry, 2011: 18(14):2146-57
• Bioorg.Med.Chem.Lett,2011,21(7), 1965-1968
• Mol Biol Rep DOI 10.1007/s 11033-011-0800-8
• Physical Chemistry chinese Science Bulletin. 2011 Vol.56 No.1: 1–6
• Bioorganic & Medicinal Chemistry Letters, 2011, 21, 2949-2952
• Protein Sci. 2011 Apr; 20(4):735-44
• J Med Chem. 2012 Mar 8; 55(5):2144-53
• Bioorganic & Medicinal Chemistry Letters, 2012, 22, 1208-1212
• J. Med. Chem. 2012, 55 (5), pp 2144–2153
• J. Med. Chem. 2012, DOI: 10.1021/jm201591k
• Current Pharmaceutical Design, 2012, 18, 3421-3431
• European Journal of Medicinal Chemistry 49 (2012) 164-171
• Int. J. Mol. Sci. 2012, 13, 6620-6638
• 200910039366.9
• 200910039897.8
• PCT/CN2009/000243
• 201010216603.7
• 201010600967.5
• 201110007772.4
• GIBH Drug Discovery Pipeline, DDP Construction 2010
• GIBH Drug Discovery Pipeline, DDP Construction (Phase Ⅱ) 2011
• Thousands of People Plan “High-end Foreign Experts Project 2012
• NSFC Grant for Synthesis of New Nucleoprotein Small Molecule Inhibitors 2012
• NSFC/NIH R01 Grant for Anti-Malaria Research 2014
• NSFC Research Grant to Study Chonrogenesis 2014
• SCCIP for the development of GIBH-130
• Guangzhou Shunjian Pharma, Inc. for the development of GZ-824
• 200910031106.7
• PCT/CN2011/000935
• 201110156399.9
• 201110267163.2
• 2011103351754
• 201210236713.9
• 201210265997.4
• 201110007547.0
• 201210202059.X
• 200710028696.9
• 200910039442.6
• 200910030051.8
• 201010279888.9
• PCT/CN2010/076652
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Innovation in the drug discovery pipeline
Models for Collaboration
40
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R&D Partner
Lead Opt. Candidate
Hit Identification
New Target ID
Drug Repositioning
Licensing GIBH Candidates
Contract Research
Assay Development
In Vivo Pharmacology
PK
HTS
Collaboration policies are flexible at GIBH; Open to many different types of agreements
De nova drug discovery Reliable partner in China
Drug Discovery Requires Patience
41
Idea! Drug
• Traditional
Med.
Chem.
• Rational
drug design
• In vitro
• Ex vivo
• In vivo
• In silico
• High
throughput
U.S (FDA)
E.U. (EMEA)
Japan
(MHLW)
China
(cFDA)
• Testing
starts at
Phase I
(Phase
I/II/III
• Bioavailabili
ty
• Systemic
exposure
Target
Discovery
Discovery
& Screening
Lead
Optim. ADMET Development Registration
2-3 yr 1-2 yr 1-3 yr 1-2 yr 5-6 yr 1-2 yr
• Expression
analysis
• In vitro
function
• In vivo
validation
• Bioinformat
ics
Preclinical validation and drug selection
(5 to 10 Years)
Clinical & drug approval
(6 to 8 Years)
Drug discovery is a long process that requires patience, long term commitment and investment!
Infra-structure and integration of core technologies is critical for doing proper drug development and has
been achieved at GIBH
Many Institutes in the USA and Europe have been successful - Northwestern with Lyrica, Florida State
with synthetic Taxol, and many more example to inspire us to move forward
60% of new drugs originally come from Institutes and small bio-tech
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Drug
Discovery
Center
Stem Cell
Institute
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HBridging with the Stem Cell Institute
Innovative drug discovery using stem cells for new target ID and compound screening
A. Tissue bank of induced pluripotent stem cells from well defined diseased patient populations
B. Robust protocols for somatic cell differentiation including neurons, hepatocytes,
cardiomyocytes and others cell types
C. Cell phenotype analysis via high content screening
D. Compound library screening for phenotype modulation
Analyzing Diseased Linked SNPs or
Splice Variants using iPSC 43
Tissue Bank
150 iPS cell Lines
iPSC Expansion
Rapid identification of
hetero- and mono-
zygote clones carrying
the SNP or SV by PCR
Expression of gene
containing SNP or SV
by qPCR and WB
Efficient neuronal
differentiation
Phenotype
Analysis
Drug
Screening
SNP or SV Wild type Hetero Mono Expression Phenotype
rs1 14 20 3 Confirmed In Progress
rs2 22 25 6 In Progress In Progress
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SNPs and SVs linked to CNS diseases are currently being evaluated at GIBH