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New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design, Synthesis and Biological Evaluation.

ABSTRACT: Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure-activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.

SUBMITTER: Oyallon B

PROVIDER: S-EPMC7914722 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design, Synthesis and Biological Evaluation.

Oyallon Bruno B Brachet-Botineau Marie M Logé Cédric C Robert Thomas T Bach Stéphane S Ibrahim Sajida S Raoul William W Croix Cécile C Berthelot Pascal P Guillon Jean J Pinaud Noël N Gouilleux Fabrice F Viaud-Massuard Marie-Claude MC Denevault-Sabourin Caroline C

Molecules (Basel, Switzerland) 20210206 4

Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure-activity relationships (SAR) an ...[more]

PMID: 33562106

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Project description:Novel quinoxaline derivatives (2a-d, 3, 4a, 4b and 5-15) have been synthesized via the reaction of 4-methyl-3-oxo-3,4-dihydroquinoxaline-2-carbohydrazide (1) with different aldehydes, ketones, diketones, ketoesters, as well as hydrazine, phenyl isothiocyanate, carbon disulphide. The synthesized products have been screened for their in vitro anticancer and COX inhibitory activities. Most of the synthesized compounds exhibited good anticancer and COX-2 inhibitory activities. MTT assay revealed that compounds 11 and 13 were the most potent and exhibited very strong anticancer activity against the three cancer cell lines with IC50 values ranging from 0.81 μM to 2.91 μM. Compounds 4a and 5 come next and displayed strong anticancer activity against the three cancer cell lines with IC50 values ranging from 3.21 μM to 4.54 μM. Mechanistically, compounds 4a and 13 were the most active and potently inhibited EGFR with IC50 = 0.3 and 0.4 μM, respectively. Compounds 11 and 5 come next with IC50 = 0.6 and 0.9 μM, respectively. Moreover, compounds 11 and 13 were the most potent as COX-2 inhibitors and displayed higher potency against COX-2 (IC50 = 0.62 and 0.46 μM, respectively) more than COX-1 (IC50 = 37.96 and 30.41 μM, respectively) with selectivity indexes (SI) of 61.23 and 66.11, respectively. Compounds 4a and 5 comes next with IC50 = 1.17 and 0.83 μM and SI of 24.61 and 48.58, respectively. Molecular docking studies into the catalytic binding pocket of both protein receptors, EGFR and COX-2, showed good correlation with the obtained biological results. Parameters of Lipinski's rule of five and Veber's standard were calculated and revealed that compounds 4a, 5, 11 and 13 had a reasonable drug-likeness with acceptable physicochemical properties. Therefore, based on the obtained biological results accompanied with the docking study and physicochemical parameters, it could be concluded that compounds 4a, 5, 11 and 13 could be used as promising orally absorbed dual anti-inflammatory agents via inhibition of COX-2 enzyme and anticancer candidates via inhibition of EGFR enzyme and could be used as a future template for further investigations.

Dataset Information

New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design, Synthesis and Biological Evaluation.

Publications

New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design, Synthesis and Biological Evaluation.

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