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, XH-30 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 in vivo (TGI = 58%).
Additionally, XH-30 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, XH-30, which provides a novel therapeutic option for treating
P53-mutated TNBC.