SRA141 – A SELECTIVE CDC7 INHIBITOR
SRA141 is a potent, highly selective, orally available small molecule inhibitor of cell division cycle 7 kinase (Cdc7). SRA141’s selectivity profile offers possible differentiation and potential safety and efficacy advantages.
Cdc7 is a serine-threonine kinase which acts as a key regulator of both DNA replication and is involved in the DDR network. Over-expression of Cdc7 and its partner proteins is correlated with unfavorable clinical outcomes and poor survival in a broad range of solid tumors and hematological malignancies. Inhibition of Cdc7 has been shown to cause cancer cell death in a p53-independent manner, and to induce tumor stasis or regression in a variety of in vivo cancer models.
Cdc7, together with its partner proteins Dbf4 or Drf1, is responsible for activating DNA replication during S phase through phosphorylation of the MCM2-7 helicase. Cdc7 also stabilizes stalled replication forks and indirectly regulates the S phase DNA damage checkpoint by phosphorylating claspin, an essential Chk1 adaptor protein.
Normal cells activate a p53-dependent cell cycle arrest in response to transient Cdc7 inhibition, whereas tumor cells undergo apoptosis via checkpoint failure; this differential response provides a potential opportunity for a therapeutic window as demonstrated in preclinical studies.
Sierra Oncology is pursuing a robust program of preclinical studies with SRA141 to evaluate tumor responses and dosing regimens across a variety of indications in order to inform our clinical development plans and patient selection strategies. Preclinical data and published literature suggest a variety of solid tumors and hematological malignancies with potential for response to Cdc7 inhibitors. A biomarker-driven patient selection strategy focusing on drivers of replication stress, genomic instability and proliferation (e.g. p53, BRCA, MYC, KRAS, etc.) may help facilitate clinical trial execution.
SRA141 interacts with DNA replication and the DDR network in a different, potentially complementary way to SRA737. Inhibiting both Chk1 and Cdc7 simultaneously may be advantageous and presents the potential for novel proprietary combination strategies for SRA737 and SRA141.