Discovery of CZS-241: A Potent, Selective, and Orally Available Polo-Like Kinase 4 Inhibitor for the Treatment of Chronic Myeloid Leukemia

  • J Med Chem. 2023 Feb 3. doi: 10.1021/acs.jmedchem.2c02124.
Yin Sun  1 ,  Yanli Xue  1 ,  Hongbing Liu  2 ,  Shuyi Mu  1 ,  Pengkun Sun  1 ,  Yu Sun  1 ,  Lin Wang  1 ,  Hanxun Wang  1 ,  Jingkai Wang  1 ,  Tianxiao Wu  1 ,  Wenbo Yin  1 ,  Qiaohua Qin  1 ,  Yixiang Sun  1 ,  Huali Yang  1 ,  Dongmei Zhao  1 ,  Maosheng Cheng  1
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, P. R. China.
  • 2. School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, P. R. China.
PMID: 36734825 DOI: 10.1021/acs.jmedchem.2c02124
Abstract

Recent studies demonstrate that PLK4 has emerged as a therapeutic target for the treatment of multiple cancers owing to its indispensable role in cell division. Herein, starting from previously identified effective compound CZS-034, based on rational drug design strategies, tyrosine kinase receptor A (TrkA) selectivity- and metabolic stability-guided structure-activity relationship (SAR) exploration were carried out to discover a highly potent (IC50 = 2.6 nM) and selective (SF = 1054.4 over TrkA) PLK4 Inhibitor B43 (CZS-241) with acceptable human liver microsome stability (t1/2 = 31.5 min). Moreover, compound B43 effectively inhibited leukemia cells in 29 tested cell lines, especially chronic myeloid leukemia (CML) cell lines K562 and KU-812. Pharmacokinetic characteristics revealed that compound B43 possessed over 4 h of half-life and 70.8% bioavailability in mice. In the K562 cells xenograft mouse model, a 20 mg/kg/day dosage treatment obviously suppressed tumor progression. As a potential and novel PLK4-targeted candidate drug for CML, compound B43 is undergoing extensive preclinical safety evaluation.

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