Small Molecules Targeting the Inactive Form of the Mnk1/2 Kinases

ACS Omega
Srinivasaraghavan KannanChandra S Verma

Abstract

Overexpression of the eukaryotic initiation factor 4E (eIF4E) is linked to a variety of cancers. Both mitogen-activated protein kinases-interacting kinases 1 and 2 (Mnk1/2) activate the oncogene eIF4E through posttranslational modification (phosphorylating it at the conserved Ser209). Inhibition of Mnk prevents eIF4E phosphorylation, making the Mnk-eIF4E axis a potential therapeutic target for oncology. Recently, the design and synthesis of a series of novel potent compounds inhibiting the Mnk1/2 kinases were carried out in-house. Here, we describe computational models of the interactions between Mnk1/2 kinases and these inhibitors. Molecular modeling combined with free energy calculations show that these compounds bind to the inactive forms of the kinases. All compounds adopt similar conformations in the catalytic sites of both kinases, stabilized by hydrogen bonds with the hinge regions and with the catalytic Lys78 (Mnk1) and Lys113 (Mnk2). These hydrogen bond interactions clearly play a critical role in determining the conformational stability and potency of the compounds. We also find that van der Waals interactions with an allosteric pocket are key to their binding and potency. Two distinct hydration sites that appear to f...Continue Reading

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Citations

May 15, 2018·Current Medicinal Chemistry·Xiao HuAlessandro Contini
Jun 11, 2020·International Journal of Molecular Sciences·Sathyen A PrabhuSonia V Del Rincón
Apr 24, 2021·European Journal of Medicinal Chemistry·Xin JinTao Jiang
Oct 8, 2020·Journal of Natural Products·Liang-Chieh ChenKai-Cheng Hsu
Sep 18, 2021·Journal of Medicinal Chemistry·Weijun XuKassoum Nacro

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