Discovery of PKMYT1 Inhibitors with a Novel Scaffold for the Treatment of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a refractory tumor characterized by a high mutation rate of the P53 gene, leading to an increased reliance on the G2/M checkpoint to maintain genomic integrity in response to DNA damage. PKMYT1 is highly expressed in TNBC and serves as a crucial regulator of the G2/M checkpoint. Therefore, inhibiting PKMYT1 may be an effective strategy for treating P53-mutated TNBC. Herein, we report a series of PKMYT1 inhibitors featuring a novel scaffold. Among these compounds, <b>XH-30</b> exhibited significant PKMYT1 inhibitory activity (IC₅₀ = 4.1 nM) and induced G2/M phase release in MDA-MB-231 cells (a P53-mutated TNBC cell line), demonstrating promising antitumor effects <i>in vivo</i> (TGI = 58%). Additionally, <b>XH-30</b> achieves a synergistic antitumor effect with the PARP1 inhibitor Olaparib by downregulating the expression of BRCA1/2. In conclusion, we have identified a potent PKMYT1 inhibitor, <b>XH-30</b>, which provides a novel therapeutic option for treating P53-mutated TNBC.