Novel Carboxamide-Based PKMYT1 Inhibitors for Replication Stress-Associated Cancers

Abstract Protein kinase membrane associated tyrosine/threonine 1 (PKMYT1) is a key regulator of the G2/M cell cycle checkpoint that suppresses CDK1 activity in response to DNA damage and replication stress. Pharmacological inhibition of PKMYT1 induces premature mitotic entry, accumulation of DNA damage, and cancer cell death, and may enhance the efficacy of ATR inhibitors, PARP inhibitors, chemotherapy, and radiotherapy. This patent overview summarizes the design, synthesis, and therapeutic potential of novel carboxamide-based PKMYT1 inhibitors for the treatment of replication stress-associated cancers.