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Inhibitors of Cdc7
- In vivo single agent efficacy and PD biomarker modulation via oral route.
- Two highly potent and selective structurally distinct series in lead optimisation.
- Good ADME and in vivo mouse pharmacokinetic profile.
CRUK Commercial Partnerships is seeking a partner to progress our lead compounds to clinical investigation for development of Cdc7 inhibition-based cancer therapy.
Two distinct chemical series of novel, orally bioavailable and selective small molecule inhibitors have been identified and are undergoing lead optimisation. Both series show excellent potency, efficacy and modulation of a pharmacodynamic (PD) biomarker both in vitro and in vivo. High resolution cocrystal structures with both series lead compounds bound to Cdc7 have been determined.
Key to differentiating CRUK’s programme from competitor compounds both in the clinic and in preclinical development is the high selectivity of our inhibitors. Profiling of compounds against a diverse panel of kinases demonstrated excellent selectivity and no inhibition of other cell cycle kinases.
In phenotypic assays using colorectal cancer cells, CRUK’s Cdc7 inhibitors induce a pronounced decrease in proliferation and an abortive S phase progression followed by an increase in apoptotic cells. In contrast, normal fibroblasts treated with Cdc7 inhibitors remain viable and show no evidence of apoptosis, despite showing equivalent modulation of the in vivo biomarker, thus demonstrating that inhibition of Cdc7 with our compounds results in tumour cell-specific killing.
Uncontrolled proliferation and cell cycle progression is a hallmark of cancer and the DNA replication licensing system
has emerged as a powerful mechanism for controlling cell proliferation.
Cdc7, a serine/threonine kinase, is a core component of the licensing machinery required for origin unwinding of the DNA and recruitment of DNA polymerases required for DNA synthesis. It is essential for initiating DNA replication via phosphorylation of the MCM2 complex and has a well demonstrated role in DNA damage response and
post-replication DNA repair.
Inhibition of Cdc7 selectively induces cell death in a variety of tumours while only inducing a reversible cell cycle arrest in normal cells. Indeed, depletion of Cdc7 in cancer cell lines has been demonstrated to cause an abortive S phase and apoptotic cell death or aberrant mitosis. In contrast, in untransformed cells Cdc7 depletion results in a reversible arrest in G1 or a prolongation of S-phase and cells remain in a viable non-proliferative state.