Structure-Based\nDrug Design of 2‑Amino-[1,1′-biphenyl]-3-carboxamide\nDerivatives as Selective PKMYT1 Inhibitors for the Treatment of <i>CCNE1</i>-Amplified Breast Cancer

<i>CCNE1</i> amplification occurs in breast cancer and\ncurrently lacks effective therapies. PKMYT1 as a synthetic lethal\ntarget for <i>CCNE1</i> amplification holds promise for\nthe treatment of <i>CCNE1</i>-amplified breast cancer. Herein,\nwe discover a series of 2-amino-[1,1′-biphenyl]-3-carboxamide\nderivatives as potent and selective PKMYT1 inhibitors using structure-based\ndrug design. The representative compound <b>8ma</b> exhibited\nexcellent potency against PKMYT1, while sparing WEE1. It also suppressed\nproliferation of the <i>CCNE1</i>-amplified HCC1569 breast\ncancer cell line and showed synergistic cytotoxicity in combination\nwith gemcitabine. PKMYT1 X-ray cocrystallography confirmed that introduction\nof key binding interactions between the inhibitors and residues Asp251\nand Tyr121 of PKMYT1 greatly enhanced the potency and selectivity\nof the compounds.