Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that catalyses the synthesis of poly (ADP-ribose) chains from NAD+ as part of the single-strand DNA repair process. PARP-1 inhibitors have therapeutic utility in oncology through potentiation of the anti-tumor activity of radiation or DNA damaging chemotherapeutic agents, and 'targeted' therapy in BRCA-mutation associated breast cancers. We previously reported a potent pyrrolocarbazole PARP-1 HTS hit (IC50 value of 36 nM) identified from our internal library. Lead optimization on this novel chemotype to improve cellular potency, physical properties and selectivity produced lead CEP-8983. A novel Mannich base prodrug strategy led to clinical candidate CEP-9722. The synthesis, SAR and preclinical development leading to the identification of CEP-9722 will be presented.

Discovery of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor clinical candidate CEP-9722

247th National Meeting (2014)

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