Original article Identification of novel aminothiazole and aminothiadiazole conjugated cyanopyridines as selective CHK1 inhibitors Sobhi M. Gomha a, * , Mohamed M. Abdulla b , Sahar M. Abou-Seri c a Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt b Research Unit, Saco Pharm. Co., 6th October City, Egypt c Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Egypt article info Article history: Received 29 August 2014 Received in revised form 8 December 2014 Accepted 9 January 2015 Available online 10 January 2015 Keywords: 2-Aminocyanopyridine 1,3,4-Thiadiazoles Hydrazonoyl halides 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 cya- nopyridyl-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. Mo- lecular 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. © 2015 Elsevier Masson SAS. All rights reserved. 1. Introduction The physiological functions and pathological conditions of the cancer cells are under the control of a number of endogenous growth factors, receptor and non-receptor kinases and checkpoints. Checkpoint kinase 1 (CHK1) is an intracellular, serine/threonine kinase that controls the cellular response to DNA damage [1,2]. Because of DNA damage by UV light, radiation, or cytotoxic drugs, a signaling cascade is triggered to halt the cell cycle and initiate DNA repair. CHK1 is activated by the upstream kinase, ataxia telangiec- tasia and rad3 related (ATR), in response to single strand breaks in DNA [3], and in turn CHK1 phosphorylates a number of down- stream proteins leading to cell cycle arrest in S-phase or at the G2/ M transition [4]. As well as establishing S and G2/M cell cycle checkpoints, CHK1 also promotes homologous recombination repair of damaged DNA [5]. Cell cycle arrest in response to DNA damage may occur in G1, and the structurally unrelated enzyme checkpoint kinase 2 (CHK2) plays a significant part in the control of the G1 checkpoint [6]. The presence of alternative checkpoints and DNA repair mechanisms reduces the sensitivity of normal cells to CHK1 inhibition. Most of solid tumors are deficient for the function of the tumor suppressor p53 [7,8] or contain other defects in cell cycle checkpoints and are more reliant on the late phase cell cycle checkpoints and CHK1-mediated DNA damage response pathways as a result [9]. Inhibition of CHK1 in such p53-deficient cancer cells with damaged DNA would abrogate the cell-cycle arrest and force the progression into mitosis resulting in cell death, thus selectively sensitizing these tumor types to chemotherapy. CHK1 inhibitors are established as a potential therapy for cancer in two distinct contexts: as a single agent in specific tumors with a genetic background that leads to high levels of intrinsic DNA damage or in combination with conventional genotoxic chemo- therapy or ionizing radiation [10]. Combination therapy comprising a DNA-damaging agent with CHK1 inhibitor will potentially have significantly higher therapeutic index than chemotherapy alone. Abbreviations: ATP, adenosine triphosphate; ATR, ataxia telangiectasia and rad3 related; CDK1, cyclin dependent kinase 1; CHK1, checkpoint kinase 1; CHK2, checkpoint kinase 2; DELFIA, dissociation-enhanced lanthanide fluorescent immunoassay; ELISA, enzyme-linked immunosorbent assay; hERG, human ether-a- go-go related gene product; MLM, mouse liver microsomes; MPM2, M-phase phosphoprotein 2; MYCN, V-myc myelocytomatosis viral related oncogene, neu- roblastoma derived; RNAi, RNA interference; SRB, sulforhodamine B. * Corresponding author. E-mail address: s.m.gomha@hotmail.com (S.M. Gomha). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2015.01.019 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 92 (2015) 459e470