Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia.

Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia. ChemMedChem. 2021 Feb 16;: Authors: Jin T, Wang P, Long X, Jiang K, Song P, Wu W, Xu G, Zhou Y, Li J, Liu T Abstract Checkpoint kinase 1 (CHK1) is a central component in DNA damage response and has emerged as a target for antitumor therapeutics. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent diaminopyrimidine CHK1 inhibitors. The compounds exhibited moderate to potent CHK1 inhibition and could suppress the proliferation of malignant hematological cell lines. The optimized compound 13 had a CHK1 IC50 value of 7.73±0.74 nM, and MV-4-11 cells were sensitive to it (IC50 =0.035±0.007 μM). Furthermore, compound 13 was metabolically stable in mouse liver microsomes in vitro and displayed moderate oral bioavailability in vivo. Moreover, treatment of MV-4-11 cells with compound 13 for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Based on these biochemical results, we consider compound 13 to be a promising CHK1 inhibitor and potential anticancer therapeutic agent. PMID: 33591599 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research