Our Science

Cleave Therapeutics’ novel VCP/p97 inhibitors exploit molecular features that are key to supporting cancer cell growth and metabolism. VCP/p97 plays a critical role in protein homeostasis processes such as endoplasmic reticulum associated degradation (ERAD) and chromatin associated degradation (CAD), as well as the DNA damage response (DDR).^II These key cellular stress pathways are known to represent sensitivities critical to cancer cell survival. Cellular stress provides an attractive means of targeting non-oncogene addiction as a way to combat tumor heterogeneity and emerging resistance to targeted therapies. Such an approach has the added benefit of broad applicability, not dependent on a single driver mutation and potential efficacy across a range of cancer types.

Key results from various academic and government labs support the potential for VCP/p97 as a viable target in oncology, and recent results from large scale CRISPR screens performed by the Wellcome Sanger Institute identifying VCP/p97 as a pan-cancer core fitness gene in over 300 cell lines across 13 cancer types furthers this rationale.^I  Drugging these pathways provides a potential new therapeutic route for patients fighting cancer. VCP/p97 is an important cellular AAA ATPase that has a well described role as a master regulator in the Ubiquitin Proteasome System where it extracts misfolded proteins from membranes or protein complexes and chaperones them to the proteasome for degradation.^II 

VCP/p97 has also been shown to play a critical role in chromatin remodeling and the response to DNA damage.^III-IV Emerging evidence suggests that cancer cells become over-dependent on protein homeostasis pathways for growth and survival, and therefore, inhibitors of VCP are expected to have meaningful anti-cancer activity.^V Genetic knockdown of VCP leads to cell death in a number of solid tumor cell lines and compounds that inhibit VCP have been shown to drive cancer cell death in various pre-clinical models.^VI-X