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

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.