2. Academic Validation
  3. Discovery of Tetracyclic Derivatives as Highly Potent, Selective, and Bioavailable PKMYT1 Inhibitors for Cancer Therapy

Discovery of Tetracyclic Derivatives as Highly Potent, Selective, and Bioavailable PKMYT1 Inhibitors for Cancer Therapy

  • J Med Chem. 2026 Jan 22;69(2):1004-1032. doi: 10.1021/acs.jmedchem.5c01298.
Wei Zhu 1 2,  Lei Jiang 1 2,  Dongxing Zhu 1 2,  Lu Liu 1 2,  Jianbin Xue 1 2,  Tao Wang 1 2,  Yike Zhou 1 2,  Hao Zhang 1 2,  Baoying Cheng 1 2,  Shuo Qian 1 2,  Jinwen Shan 1 2,  Mengying Li 1 2,  Wenjing Li 1 2,  Jianing Song 1 2,  Liting Xue 1 2,  Zhengtao Li 1 2,  Renhong Tang 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Neurology and Oncology Drug Development, Nanjing 210042, China.
  • 2 Simcere Zaiming Pharmaceutical Co, Ltd., Shanghai 201321, China.
PMID: 41468420 DOI: 10.1021/acs.jmedchem.5c01298
Abstract

PKMYT1 represents a promising therapeutic target for CCNE1-amplified cancers due to its synthetic lethal relationship with CCNE1. By leveraging a structure-based drug design strategy, we successfully developed a series of novel, highly potent and selective PKMYT1 inhibitors. Notably, compound 20 exhibited potent antiproliferative activity in CCNE1-amplified cell lines while showing minimal effects on their wild-type counterparts, along with exceptional selectivity across a broad kinase panel. Moreover, its favorable pharmacokinetic properties contributed to robust antitumor efficacy in an HCC1569 xenograft model. Furthermore, two prodrug derivatives of compound 20 were designed to improve aqueous solubility, achieving dose-proportional systemic exposure in rats during dose-escalation preclinical toxicity studies. Additionally, the combination of prodrug 22 with TrodelvyⓇ, a TROP2 ADC, demonstrated synergistic antitumor activity in triple-negative breast Cancer MDA-MB-231 xenograft models.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-181004
    PKMYT1 Inhibitor
    CDK