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RHPS4

RHPS4. Cardiovascular toxicity: hERG = 200 nM Muscarinic receptor liabilities. RHPS4. Back-up plan initiated………………. Criteria for New Candidate. Q/D Affinity & Selectivity (SPR). = RHPS4 or better (32). Solubility. > 5 mg/mL.

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RHPS4

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  1. RHPS4 Cardiovascular toxicity: hERG = 200 nM Muscarinic receptor liabilities RHPS4 Back-up plan initiated………………

  2. Criteria for New Candidate Q/D Affinity & Selectivity (SPR) = RHPS4 or better (32) Solubility > 5 mg/mL Colorectal, Melanoma, Breast lines with varying telomere length hERG CEREP (Inc’ muscarinics) GI50 > 30 uM GI50 Normal Fibroblast GI50(Norm) /GI50(Canc) - Ratio > 20 Rat PO evaluation > 20 % Xeno T/C > 20 %

  3. Screening data – Re-visit Profile against hERG

  4. hERG data Full DR

  5. Chemistry Plans - hERG • 18.5 – 90 times less hERG active = less cardiotoxicity* • More selective for desired target. • Cellularly more active IH466 IH383 hERG IC50= 18 uM hERG IC50= 3.7 uM • Small focussed library – amides, sulfonamides – Intended to maintain an ‘acidic’ amidic proton modulate lipophilicity. • Focus on Q/D ratio and hERG in first instance – Training set of compounds

  6. Telomere Targeting Agents Submitted for hERG & Q/D testing

  7. hERG affinities – Training set

  8. hERG Drivers – Lipophilicity Design space RHPS4

  9. Quadruplex Affinities

  10. Current Work Designed to reduce lipohilicity, while reducing basicity of central core

  11. Demonstrated that hERG liability can be reduced while maintaining desired affinity. Main hERG driver for this chemotype is lipophilicity. Currently synthesising less lipophilic 3-derivatives – Molecular model suggests more space available for diversity at this position. Awaiting duplex DNA affinity data before next design phase. Need to explore muscarinic liability. Summary

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