Oncology Targets

Provid and the National Cancer Institute entered into a collaboration to design and develop novel, selective inhibitors of checkpoint-2 kinase, a target in the cell cycle pathway of interest in cancer therapy.

Chk2 inhibitors are expected to be synergistic with chemotherapy and radiation and to protect normal cells from DNA damage in therapy.  In addition, some tumor cell types are dependent on Chk2, suggesting a primary inhibitory activity of a Chk2 inhibitor.

The research phase of the project was described in detail in a publication by the NCI and Provid teams:
Cellular inhibition of checkpoint kinase 2 (Chk2) and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019 [7-nitro-1H-indole-2-carboxylic acid {4- [1-(guanidinohydrazone)-ethyl]-phenyl}-amide], J Pharmacol Exp Ther. 2009 Dec;331(3):816-26 (view this article on PubMed).

Provid's lead inhibitor, PV-1019 is highly selective for Chk2 over other kinases and has demonstrated activity in cellular assays as described in this publication.  The project was a classic example of expert medicinal chemistry and structure-based drug design.  Compounds produced by Provid were co-crystallized with the Chk2 enzyme at NCI and multiple structures of the complexes were obtained and used in iterative cycles of optimization.  Future work will involve selection and refinement of pharmaceutical properties of a drug candidate in this series.  A US patent application has been filed and is currently being prosecuted.