title: Identification of novel aminothiazole and aminothiadiazole conjugated cyanopyridines as selective CHK1 inhibitors.
abstract: Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential anti-tumor agents. Novel series of cyanopyridyl-aminothiadiazoles (synthesized from reaction of 1-(3-cyano-4,6-diphenylpyridin-2-yl)-3-phenylthiourea (14) with hydrazonoyl halides) and cyanopyridyl-aminothiazolyl-thiadiazoles (synthesized from treatment of 14 with ethyl chloroacetate followed by reaction of the obtained cyanopyridyl-aminothiazole with hydrazonoyl halides) were synthesized and evaluated for their CHK1 inhibitory potential using a cell-based assay cascade. The tested compounds exhibited a potent and selective CHK1 inhibitory activity at nanomolar levels that reflected their ability to abrogate cell cycle arrest and potentiate the cytotoxic effect of the genotoxic drug gemcitabine in colon cancer cells. Molecular modeling simulation revealed that, the most active compound 28a docked well into the enzyme active site and their complex is stabilized by a key H-bonding with the backbone amide of Cys-87 as well as multiple favorable hydrophobic interactions with different hydrophobic binding regions of the enzyme.
authors.affiliation: Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt. Electronic address: s.m.gomha@hotmail.com.
authors.forename: Sobhi M
authors.initials: SM
authors.lastname: Gomha
authors.affiliation: Research Unit, Saco Pharm. Co., 6th October City, Egypt.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Abdulla
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Egypt.
authors.forename: Sahar M
authors.initials: SM
authors.lastname: Abou-Seri
mesh_terms: D000071877:Checkpoint Kinase 1; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013830:Thiadiazoles; C010852:2-amino-1,3,4-thiadiazole; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: 1,3,4-Thiadiazoles; 2-Aminocyanopyridine; Hydrazonoyl halides; Selective CHK1 inhibitors