Discovery of CZS-241: A Potent, Selective, and Orally Available Polo-Like Kinase 4 Inhibitor for the Treatment of Chronic Myeloid Leukemia.
Yin SunYanli XueHongbing LiuShuyi MuPengkun SunYu SunLin WangHanxun WangJingkai WangTianxiao WuWenbo YinQiaohua QinYixiang SunHuali YangDongmei ZhaoMaosheng ChengPublished in: Journal of medicinal chemistry (2023)
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 (IC 50 = 2.6 nM) and selective (SF = 1054.4 over TRKA) PLK4 inhibitor B43 (CZS-241) with acceptable human liver microsome stability ( t 1/2 = 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.
Keyphrases
- chronic myeloid leukemia
- tyrosine kinase
- induced apoptosis
- mouse model
- acute myeloid leukemia
- emergency department
- bone marrow
- adipose tissue
- risk assessment
- climate change
- combination therapy
- endoplasmic reticulum stress
- cell death
- drug delivery
- skeletal muscle
- cancer therapy
- drug induced
- smoking cessation
- wild type