Structure-Based Drug Design of 2-Amino-[1,1'-biphenyl]-3-carboxamide Derivatives as Selective PKMYT1 Inhibitors for the Treatment of -Amplified Breast Cancer.

amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for amplification holds promise for the treatment of -amplified breast cancer. Herein, we discover a series of 2-amino-[1,1'-biphenyl]-3-carboxamide derivatives as potent and selective PKMYT1 inhibitors using structure-based drug design. The representative compound exhibited excellent potency against PKMYT1, while sparing WEE1. It also suppressed proliferation of the -amplified HCC1569 breast cancer cell line and showed synergistic cytotoxicity in combination with gemcitabine. PKMYT1 X-ray cocrystallography confirmed that introduction of key binding interactions between the inhibitors and residues Asp251 and Tyr121 of PKMYT1 greatly enhanced the potency and selectivity of the compounds.