PLK4 (polo-like kinase 4) is an enzyme that encodes a member of the polo family of serine/threonine protein kinases. Importantly, PLK4 protein localizes to centrioles—complex microtubule-based structures found in centrosomes-and regulates centriole duplication during the cell cycle. Particularly, PLK4 has been regarded as an extremely potential anticancer target, and is overexpressed in several cancers, including breast, lung, colorectal, and glioblastoma.
In this article, we will introduce an orally active and selective inhibitor of PLK4, CZS-241.
CZS-241 is a potent, selective and oral active PLK4 inhibitor with IC50 values of 2.6, 2741.4 nM for PLK4, TRKA, respectively. Besides, This compound inhibits cell proliferation of chronic myeloid leukemia (CML) cell lines K562 and KU-812 with IC50s of 0.096 μM and 0.25 μM, respectively. In addition, CZS-241 has little effect on normal cells including HUVECs and L02. Moreover, CZS-241 (10 μM; 0-120 min) exhibits 31.5 min of half-life t1/2 and 41.8 μL/min/kg of CLint in human liver microsomal. Meanwhile, CZS-241 (0.3 μM, 1 μM, 3 μM; 48 h) arrests the cell cycle at the S/G2 phase, and induces apoptosis in K562 CML cells. Additionally, CZS-241 (0.03-0.3 μM) inhibits the phosphorylation of PLK4, and increases the FBXW5 expression level but decreases the SAS-6 expression level in K562 cells.
CZS-241 also shows antitumor activity in vivo. For example, CZS-241 (30 mg/kg; p.o.; single dose) shows over 4 h of half-life and 70.8% bioavailability in mice and CZS-241 (20 mg/kg/day; p.o.; 21 days) suppresses tumor progression significantly in K562 cells xenograft mouse model. Besides, CZS-241 (200 mg/kg; p.o.; single dose) has no obvious signs of toxicity in the heart, liver, spleen, lungs, and kidneys of mice, within 7 days of monitoring.
All in all, CZS-241 is an orally active and selective inhibitor of PLK4. Moreover, CZS-241 has the potential for the research of chronic myeloid leukemia.