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

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 (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.

Discovery of BWA-522, a First-in-Class and Orally Bioavailable PROTAC Degrader of the Androgen Receptor Targeting N-Terminal Domain for the Treatment of Prostate Cancer

“…In addition to hepatic metabolism, compounds will also be subject to degradation and modification by enzymes in plasma, particularly hydrolases and esterases . Hence, the plasma stability was also determined by incubating BWA-522 with mouse and human plasma at six different time points at 0, 15, 30, 45, 60, and 120 min.…”

“…In addition to hepatic metabolism, compounds will also be subject to degradation and modification by enzymes in plasma, particularly hydrolases and esterases. 61 Hence, the plasma stability was also determined by incubating BWA-522 with mouse and human plasma at six different time points at 0, 15, 30, 45, 60, and 120 min. The results are shown in Tables 8 and S2; BWA-522 remained ∼90% after a 120 min incubation, indicating that BWA-522 was highly stable in both mouse and human plasma.…”

Discovery of the First Potent, Selective, and In Vivo Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of TRIM37-Amplified Breast Cancer

“…Compound 1 (CFI-400945, IC 50 = 1.55 nM) has advanced into Phase II clinical trial but studies showed that it was not a selective PLK4 inhibitor. , To simplify the structure of CFI-400945, Yu et al utilized a scaffold hopping strategy to obtain compound 2 (YLT-11, IC 50 = 22 nM). , Compound 3 (centrinone or LCR-263) was developed by Oegema et al in 2015 with an IC 50 value of 2.7 nM, , and it was often used as a positive control. Recently, our research group reported three PLK4 inhibitors: Type-I inhibitors 4 (CZS-034, IC 50 = 0.2 nM) and 5 (CZS-241, IC 50 = 26 nM), Type-II inhibitor 6 (CZS-089, IC 50 = 26 nM). CZS-034 potently bound with PLK4 protein and exhibited stronger antiproliferation activity in TRIM37 -amplified breast cancer cells than CZS-241 and CZS-089.…”

“…29,30 Compound 3 (centrinone or LCR-263) was developed by Oegema et al in 2015 with an IC 50 value of 2.7 nM, 31,32 and it was often used as a positive control. Recently, our research group reported three PLK4 inhibitors: Type-I inhibitors 4 33 (CZS-034, IC 50 = 0.2 nM) and 5 34 (CZS-241, IC 50 = 26 nM), Type-II inhibitor 6 35 (CZS-089, IC 50 = 26 nM). CZS-034 potently bound with PLK4 protein and exhibited stronger antiproliferation activity in TRIM37-amplified breast cancer cells than CZS-241 and CZS-089.…”

Design, synthesis, and biological evaluation of novel pyrimidin-2-amine derivatives as potent PLK4 inhibitors

“…25 In our previous studies, centrinone showed poor liver microsomal stability ( t 1/2 = 5.8 min) and strong cytochrome P450 (CYPs) inhibition (Tables S1 and S2†), which suggested that its drug-like properties need to be further optimized. 29 In addition, centrinone contains nitrobenzene, resulting in a potential safety issue, which may be one of the reasons why it has not entered clinical research. Therefore, we hope to obtain novel, safe and effective small molecule PLK4 inhibitors through the structural modification of centrinone (Fig.…”