Identification of novel, selective and potent Chk2 inhibitors
Graphical abstract
Novel, selective and potent Chk2 inhibitors were identified. Their SAR and computer modeling studies were conducted.
Section snippets
Acknowledgments
The authors want to acknowledge Dr. D. Delia of Instituto Nazionale Tumori, Italy, for helping biological characterization and Dr. D. Smith for initially evaluating compounds.
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Cited by (34)
Isothiazoles
2021, Comprehensive Heterocyclic Chemistry IVRecent Advances in the Synthesis and Reactivity of Isothiazoles
2019, Advanced Synthesis and CatalysisPart II: New candidates of pyrazole-benzimidazole conjugates as checkpoint kinase 2 (Chk2) inhibitors
2018, European Journal of Medicinal ChemistryCitation Excerpt :Presence of different pyrazoles exhibited cytotoxic effect against various cancer cell lines as MCF-7, cervical carcinoma cell line (HeLa), and hepatocellular carcinoma cells (HepG2) [18–20] and acted as protein kinase modulators [21,22]. They are bioisosteres of isothiazoles carboxamidines (Fig. 1D), as VRX0466617 that displayed selective inhibition of Chk2 activity with high potency [23–25] and guanylhydrazone derivatives [26,27] as bis-guanylhydrazone[4,4-Diacetyldiphenylurea-bis(guanylhydrazone)]; NSC 109555 (Fig. 1E) [26] and [7-nitro-1H-indole-2-carboxylic acid{4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide]; PV1019 (Fig. 1E) [27] that acted as selective inhibitors of Chk2 with chemotherapeutic and radiosensitization potentials To fulfil our goals of this study, the biological activities of the synthesized compounds will be assessed both as Chk2 inhibitors and antitumor agents alone, but also in combination with cisplatin or doxorubicin.
Part I: Design, synthesis and biological evaluation of novel pyrazole-benzimidazole conjugates as checkpoint kinase 2 (Chk2) inhibitors with studying their activities alone and in combination with genotoxic drugs
2017, European Journal of Medicinal ChemistryCitation Excerpt :Isothiazole carboxamidines are simple ATP competitive inhibitors [13]. VRX0466617 is isothiazole carboxamidine derivative that exhibited potent selective inhibition for Chk2 with low Ki equivalent to 11 nM and it is useful as a radiation protection agent in anticancer radiotherapy [13,14]. Pyrazoles were reported in variety of potent anticancer active agents as Ruxolitinib (Fig. 1C) [15] which were involved in the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative disorder that affects the bone marrow [16,17].
Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein-ligand crystallography
2012, Bioorganic and Medicinal ChemistryCitation Excerpt :Recent results demonstrate that selective inhibition of CHK2 in combination with PARP inhibition could also be therapeutically beneficial in cancer therapy.3 Small molecule inhibitors of CHK2 have been disclosed including the staurosporine analogue UCN-01,4,5 an indoloazepine derivative of hymenialdisine,6 isothiazole carboxamidines,7,8 bisguanylhydrazones,9,10 the dual CHK1/CHK2 inhibitor AZD776211 as well as 3,5-diaryl-2-aminopyridines12 and 2-(quinazolin-2-yl)phenols, of which the potent and selective chemical tool CCT241553 is an example.13,14 As part of our in-house drug discovery project, we were particularly intrigued by a published series of benzimidazole CHK2 inhibitors for which two closely related binding modes have been proposed, neither of which appeared entirely consistent with the reported SAR (vide infra).15–17