2. Academic Validation
  3. Discovery of PKMYT1 Inhibitors with a Novel Scaffold for the Treatment of Triple-Negative Breast Cancer

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

  • J Med Chem. 2026 Jan 8;69(1):228-249. doi: 10.1021/acs.jmedchem.5c02263.
Jingling Huang 1,  Peixuan Li 1,  Feihuang Qiu 1,  Yingming Fu 1,  Wenxin Yan 1,  Yongling Xu 1,  Xinyu Sun 1,  Xiuhua Zhang 1,  Yi Zou 1,  Qihua Zhu 1,  Yungen Xu 2 1,  Hongfeng Gu 1
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
PMID: 41427887 DOI: 10.1021/acs.jmedchem.5c02263
Abstract

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.

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