Science

Our Science

We are leveraging our library of small molecule inhibitors of the novel target, VCP/p97, to tackle human diseases with severely unmet medical need. Targeting VCP/p9 allows us to exploit cellular dependencies on stress response pathways in cancer as VCP/p97 is a key component of multiple stress pathways that cancer cells rely on to support their abnormal growth and proliferation, disrupting these pathways has been shown to be effective in targeting cancer cells.

VCP/p97
An ATP Powered Protein Extractor

VCP/p97, a member of the AAA adenosine triphosphatase (ATPase) family of enzymes, plays a critical role in several key cellular stress response pathways. VCP/p97 harnesses the power of ATP to extract and unfold proteins destined for proteasomal degradation. Cleave Therapeutics’ novel VCP/p97 inhibitors exploit these pathways for therapeutic use in oncology and other human diseases.

VCP/p97, a Master Regulator of Protein Turnover

VCP/p97 is a master regulator of protein turnover in the cell. In the endoplasmic reticulum (ER) this is critical to maintaining protein homeostasis and adapting to ER protein stress. In the nucleus, VCP/p97 is required for the effective removal and turnover of several DNA damage response factors and for the removal of trapped PARP1 from DNA that occurs as a result of therapeutic use of PARP inhibitors. Finally, at the mitochondrial membrane, VCP/p97 is a key regulator of mitochondrial fusion, helping to maintain mitochondrial homeostasis. These processes are attractive targets for impacting human diseases like cancer and neurodegeneration.

VCP in the Nucleus
DNA Damage Response and
Genomic Stress

VCP/p97 is responsible for removal of proteins that bind to DNA during the DNA damage response (DDR). In this area, VCP/p97 has also been shown to be critical for the resolution of trapped PARP1 complexes on DNA. Targeting DDR in cancer, and particularly in HR deficient tumors in combination with PARP inhibition, could drive strong responses in solid tumor indications where exploiting DNA damage has proved successful.

VCP in the Endoplasmic Reticulum
ERAD and Protein Stress

In the ER, VCP/p97 extracts misfolded/unfolded proteins for eventual degradation by the proteasome as part of the endoplasmic reticulum associated degradation pathway (ERAD). ERAD is a key component of the cellular response to protein stress. Robust protein disposal is critical to cancer cell growth and survival and has been successfully targeted clinically with approved agents in multiple myeloma.

VCP and the Mitochondria
Mitochondrial Homeostasis
Neurodegeneration

At the mitochondria, VCP/p97 is responsible for the degradation of mitofusin proteins. These proteins are required for proper fusion of mitochondria, over-degradation from hyperactive VCP mutants has been postulated to drive fragmented mitochondria seen in neurodegenerative diseases. A VCP inhibitor may be able to restore the balance and provide therapeutic benefit for these relentlessly progressive diseases.