Bay Area Screening Center BASC and Center for Chemical Diversity CCD

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Bay Area Screening Center (BASC) andCenter for
Chemical Diversity (CCD)
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BASC/CCD Mission

• Identify novel bioactive chemical entities
• Educate and train students in state-of-the-art
  drug discovery research practices
• Enhance university-corporate partnerships for
  scientific and economic benefit

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Current Research Foci

• Target Classes
• Nuclear Hormone Receptors
• Ion Channels
• CFTR Cl- channel antagonist progressing to clinic
• Viral Parasitic Targets
• Anti-Chagas protease inhibitor in clinic
• HIV, KSHV, SARS
• GPCRs,
• Disease Area Clinical Medicine Collaborations
• National Cancer Center
• Cardiovascular Research Institute
• Gladstone Institute, Virology
• ADME/Toxicity Profiling
• Technology Development

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Workflow
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Lead Op Workflow
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Current Library Holdings

• Fully available internal collection of 220,000
  small molecules
• Culled based on ADME properties
• Library continually expanding through purchase
  synthesis
• Functionally diverse target-focused
• Natural products, peptidomimetics, novel
  scaffolds linker design, etc.
• Compound library curation
• Industry academic resource, currently 225k

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Executing a Screen
LC/MS
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Post-Screen Informatics
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Reiterative Design from Hits
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Large Scale - Low Parallel
lt10 g
lt100 g
16 Channels Load to 30 g
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Small Scale - High Parallel

• Spatial array of reactors
• Varying diversity
• 96 x 1.5 mL (mg)
• 6 x 50 mL (g)
• Temp control -40 to 240 C
• Inert atmosphere or gas reagents

• Manual addition of reagents for smaller
  libraries (up to 100s)
• Robotic Addition of reagents for larger libraries
  (up to 1000s)

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Small Scale Highly Parallel Purification
Compound Purification
Structure Verification

• Current Procedures
• Fully Automated Chromatography
• Automated ESI/APCI/MS
• Automated Fraction Pooling
• 100 to 300 samples per day
• 100 mg loading

Evaporation
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Hit to Lead

• Hit Characteristics (H compounds, requiring 1 mg)
• 1. Hit at 2.5 µM in cells with XX assay
• 2. Dose response in cells with XX assay EC50 lt 5
  µM
• 3. Confirmation of structure and purity gt85 by
  LC/MS
• Validated Hit Characteristics (L0 compounds,
  requiring 1 mg)
• 1. Good score on computational ADMET prediction
  (less than 5 of 13 possible violations)
• 2. Good score on computational REOS (rapid
  elimination of swill) model (less than 10 of 93
  possible violations)
• 3. No evident cytotoxicity in 4 human cell lines
  at dose of 10 µM or 10 fold above EC50, whichever
  is higher
• 4. Desired An evident SAR from analog by
  catalog studies
• 5. Desired Best EC50 in 1 µM to 100 nM range
• Lead Characteristics (L1 compounds, requiring 20
  mg)
• 1. A scaleable synthetic route has been developed
  that allows access to wide range of analogs and
  used to produce first round of designed analogs
• 2. An evident SAR from a combination of ABC and
  LO library compounds
• 3. Equivalent potency and efficacy for best
  compounds in short circuit analysis with human
  tissue model to activity exhibited in cell model
• 4. Good performance of at least one active
  compound in rat/mouse microsome model
• a. T1/2 in range of 15 to 60 min in standard
  model
• 5. At least 10 fold selectivity for activation of
  XX transporter relative to activation of MDR and
  SUR

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Lead Op

• Validated Lead Characteristics (L2 compounds,
  requiring 650 mg)
• 1. Significant improvement in potency and/or
  efficacy relative to initial hit at least ten
  fold ideally 100 fold or more (less than three
  cycles of chemistry to meet progress more
  requires reassertion of commitment by core
  management group)
• 2. Good performance of active compounds in dog
  and human microsome models
• a. T1/2 greater than 30 min in standard model
• 3. All active compounds positive in CaCo-2
  permeability assay Papp gt 50 nm/sec
• 4. Good performance of best active compounds in
  series in Rat PK model (Cassette Dosing, 4
  compounds, disappearance of parent)
• a. T1/2 (iv) greater than 2h
• b. Vdss 0.5-5L (standard for easy to apply drugs)
  
• c. BA greater than 30
• 5. Good performance of best actives in Rat pilot
  toxicity study (po, No pathology, clinical
  observations)
• a. MTD at least 10 fold higher than dose needed
  to obtain plasma level equal to EC50 in cellular
  model
• 6. Good performance in Rat PK model (non-Cassette
  Dosing)
• a. Cmax (po at MTD) at gt 10x the C(ED50) CL int
  lt 150 mL/min/kg, CL 0-8h lt 50 mL/min/kg
• b. Linearity of Cmax to the dosing amount.
• 7. All compounds negative in p450 inhibition
  assay at 10 fold above EC50 minimally 3A4, 2D6,
  2C9, isoforms.

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Lead Op

• Late Lead Characteristics (L3 compounds,
  requiring 10 to 100 g)
• 1. Acceptable profile in rat general toxicology
  and pharmacology model (oral route dosing
  determined by MTD/EC50)
• a. Effects on heart and respiratory rates
  acceptable
• b. Effects on metabolism
• c. No gross body weight loss
• d. Food uptake normal
• e. Urinary excretion normal
• f. Fecal excretion normal
• g. Activity level normal
• h. No significant unmanageable changes in
  clinical chemistries -- particularly pancreatic,
  liver enzymes normal
• i. No clear liver or kidney damage in
  histopathology
• j Tissue toxicities (gut? pancreas renal with
  tobramycin?)
• k. Long QT or other specific toxicity mechanisms,
  according to patient population.
• 2. Negative in Ames II genotoxicity assay and not
  inducing chromosome abnormality
• 3. All compounds negative in hERG assay
• 4. All compounds acceptable levels of P450
  up-regulation (defined as per co-TX and pt.
  Population).
• 5. Reasonable profile in ion channel panel
  (defined per scaffold)
• 6. Reasonable profile in GPCR panel (defined per
  scaffold)
• 7. Soluble in water (pH7) 100 to 10 µg/mL.