MK-4884

MK-4884 is an orally bioavailable small molecule inhibitor of the Werner syndrome ATP-dependent helicase (WRN), currently under development by Merck Sharp & Dohme (MSD). The drug is designed to exploit synthetic lethality in tumors characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status. In MSI-H cells, the loss of mismatch repair leads to the accumulation of non-canonical DNA structures, such as TA-dinucleotide repeats, which require WRN helicase for resolution during replication. Inhibition of WRN in this specific genetic context leads to catastrophic DNA double-strand breaks and selective apoptosis of cancer cells, while sparing microsatellite stable (MSS) normal cells. MK-4884 is currently being evaluated in Phase 1 clinical trials for patients with advanced or metastatic solid tumors.