USP1 inhibitor HSK39775

An orally bioavailable small molecule inhibitor of the human deubiquitinating enzyme ubiquitin specific protease 1 (USP1; ubiquitin carboxyl-terminal hydrolase 1), with potential antineoplastic activity. Upon oral administration, USP1 inhibitor HSK39775 specifically targets, binds to and inhibits the activity of USP1, thereby blocking complex formation of USP1 with USP1-associated factor 1 (UAF1), and inhibits USP1-mediated deubiquitinating activity. This may result in replication fork degradation, accumulation of mono-ubiquinated substrates, inhibition of DNA damage repair, induction of cell cycle arrest and apoptosis, and decreased survival of susceptible tumor cells. USP1, overexpressed in various tumor cell types, plays a key role in the correct folding and deubiquitylation of proteins and facilitates DNA repair via its role in regulating the Fanconi anemia complex and translesion synthesis. It plays an important role in the proliferation and survival of homologous repair deficiency (HRD)-positive tumor cells.