PH027

PH027 (also referred to as PH027-1) is a potent and selective small-molecule inhibitor of the Werner syndrome protein (WRN) helicase, currently in preclinical development by Suzhou Puzheng Pharma (also known as Puhe Biopharma). The drug is designed to exploit the synthetic lethal relationship between WRN inhibition and microsatellite instability-high (MSI-H) status in cancer cells. PH027-1 specifically inhibits the helicase activity of WRN with an IC50 of 0.8 nM, while showing no effect on its exonuclease activity. Preclinical studies have demonstrated that PH027-1 selectively inhibits the viability of MSI-H cancer cell lines, such as SW48 and HCT116, at nanomolar concentrations, while sparing microsatellite stable (MSS) cells. In vivo experiments using cell-derived xenograft (CDX) models have shown that oral administration of the compound results in dose-dependent tumor growth inhibition, with nearly complete inhibition observed at 20 mg/kg QD.