gpcr targeted drug discovery...hit discovery in vitro + in vivo pharmacodynamics target discovery...
TRANSCRIPT
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GPCR targeted drug discovery
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Grace O. Mizuno, PhD Co-Founder & CEO
Domain expert who established company’s platform
Lin Tian, PhD Co-Founder & Scientific advisorInventor of company technology
Seven Bioscience’s leadership team is made up of key scientific leaders and business experts
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Mark von Zastrow, MD, PhDScientific advisor
Kit Lam, MD, PhDScientific advisor
Friedhelm Blobel, PhDStrategic advisor
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G Protein-Coupled Receptors (GPCRs) are implicated in diseases across every therapeutic area but a majority of druggable GPCRs have not been targeted
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Not targeted (224) In clinical trials (67) Established (107)0%
10%
20%
30%
40%
50%
60%
224 druggable GPCRs have not been successfully targeted
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USABLE IN PRE-CLINICAL ANIMAL MODELS IN REAL-
TIME
REPORTS DIRECT RECEPTOR-LIGAND
DYNAMICS (TEMPORAL KINETICS)
USED TO IDENTIFY BIASED LIGANDS
USED TO INTERROGATE ALLOSTERIC
MODULATION
USED FOR ORPHAN RECEPTORS
SUITABLE FOR ALL GPCRS
Our technology ✔ ✔ ✔ ✔ ✔ ✔
Radioligand binding ✔ ✔ ✔ ✔
CRE/ SRE reporter ✔ ✔
Fluo-4 Ca2+ assays ✔ ✔
IP3 assays
cAMP assays
BRET/ FRET B-Arrestinrecruitment ✔ ✔ ✔
BRET/ FRET Dimerization ✔ ✔ ✔
Despite decades of effort, existing GPCR technologies produce compounds that often lack clinical efficacy due to their inability to readout the functional physiology of the target
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Does not require
• Structural information• Known endogenous ligand• Known g-protein coupling
pathway
Seven’s technology, GPCR biosensors, overcomes the challenges other technologies face
• Kd• Emax• Ligand binding kinetics• Receptor conformation• Constitutive activity • Allostery/ dimerization• Off-target effects
Real-time output
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hit discoveryin vitro + in vivo
pharmacodynamics target discovery
GPCR biosensors, revolutionizes drug development by enabling hit discovery and candidate development in vivo and in vitro
HIT DISCOVERY
• affinity• potency• conformation defined functional
states dimerization modulation• residence time• subtype specificity + off target effects
PRE-CLINICAL PHARMACODYNAMICS
• real-time cellular + anatomical specificity
• msec temporal resolution
POWERFUL PRE-CLINICAL MODELS
TARGET DISCOVERY
• deorphanization• in vivo target validation compatible
with genetic animal models and behavior paradigms
NEW VALIDATED TARGETS
NEW CHEMISTRY
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Tian et al., 2009Huber et al., 2012
Objec&on discrimina&on task
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The compounds that we identify have a higher probability of success in the clinic because our technology achieves answers to difficult to address pre-clinical questions
Illustration
Questions we can answer in pre-clinical animal models:• Is the pathophysiology changing in response to drug X?• What is the real-time efficacy of drug X?• What is the real-time safety profile of drug X?• Are there any off-target effects?• How does drug X perform in vivo compared to drug Y?
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*3-5 months to generate new sensor
cpGFP
cpmApple
We can explore a broad range of GPCRs since GPCR biosensors can be engineered for any GPCR including orphans
• MOR, KOR, DOR opioid • GRP (BB2) gastrin releasing
peptide • CRF corticotrophin releasing factor • DRD1, DRD2, DRD4 dopamine• 𝛽1 and 𝛽2 adrenergic • 5HT2a serotonin • A2a adenosine • MT2 melatonin • NPY neuropeptide Y• NTR neurotensin
Sensors generated to date
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• Single fluorescent protein preserves optical bandwidth for imaging with multiple sensors, even closely related receptor subtypes: target selectivity/ off-target effects
• High signal to noise ratio: easy to obtain EC50/ IC50, activation/ deactivation kinetic information in HTS format (Z-prime = 0.7 using FLIPR Tetra)
• Easy to optimize and implement for all GPCRs (class A, B, etc.) including orphans, without structural information
• Directly reflects ligand induced conformation changes which enables the identification of biased ligands
• Allows both discovery and characterization of the effect of: PAMs, NAMs, agonists, antagonists, inverse agonists
• High spatial and temporal (real-time) resolution for pre-clinical animal imaging
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Seven’s technology is unmatched, powerful and revolutionary
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Our business model integrates an in house and partnered pipeline
v Partnered drug development§ Partnered drug discovery § Partnered pre-clinical developmentà Licensing of development assets
v In house drug development*§ In house assay development§ In house drug discovery§ In house pre-clinical development à Licensing of development assets
*Possible separate target-based LLC subsidiaries
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Grace O. Mizuno, PhD