82P VRTX531: A potent inhibitor of USP1 for treatment of BRAC1/2mut and HRD+ cancers

Breast cancer accounts for the highest cancer incidence and second highest cancer-related mortality among women in the United States. Breast Cancer is often molecularly characterized by mutations in the BRCA1/2 Gene, which are the master regulators of genomic stability and are essential for accurate DNA double-strand break (DSB) repair by homologous recombination (HR). Although, targeted therapies, such as the administration of poly (ADP-ribose) polymerase (PARP) inhibitors, can effectively eliminate mutated BRCA1/2 tumors, the development of resistance in patients eventually highlights the need for innovative therapeutic strategies. USP1 is a protease in the ubiquitin-specific protease (USP) subfamily that plays a crucial role in modulating DNA damage response (DDR) pathways. USP1 is a key promoter of metastatic breast cancer, making it a therapeutically relevant target to improve patient outcomes. Inhibitory effect of the VRTX531 on USP1/UAF1 activity was assessed using Ub-Rho 110 biochemical assay. Colony Formation Assay was performed in BRCA1MT / HRD+ human breast cancer cell line MDA-MB-436. Combination synergy of VRTX531 with PARP inhibitors was evaluated in-vitro using both the cell proliferation and Colony Formation Assay. VRTX531 is a novel, potent and selective inhibitor of USP1 with an IC50 of <50 nm in biochemical assay and demonstrated nM potency across a broad range of tumor lineages, including MDA-MB-436. VRTX531 was found to be having low intrinsic clearance and desirable oral bioavailability. In combination studies with first and second-generation PARP inhibitors, VRTX531 demonstrated robust synergy. VRTX531 exhibited profound activity alone and in combination with PARP inhibitors in BRCA1/2 mut and HRD+ tumours and is currently ongoing late-preclinical studies.