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Discovery of a Novel Template, 7-Substituted 7-Deaza-4'-Thioadenosine Derivatives as Multi-Kinase Inhibitors. 2021

Karishma K Mashelkar, and Woong Sub Byun, and Hyejin Ko, and Kisu Sung, and Sushil K Tripathi, and Seungchan An, and Yun A Yum, and Jee Youn Kwon, and Minjae Kim, and Gibae Kim, and Eun-Ji Kwon, and Hyuk Woo Lee, and Minsoo Noh, and Sang Kook Lee, and Lak Shin Jeong
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.

The development of anticancer drugs remains challenging owing to the potential for drug resistance. The simultaneous inhibition of multiple targets involved in cancer could overcome resistance, and these agents would exhibit higher potency than single-target inhibitors. Protein kinases represent a promising target for the development of anticancer agents. As most multi-kinase inhibitors are heterocycles occupying only the hinge and hydrophobic region in the ATP binding site, we aimed to design multi-kinase inhibitors that would occupy the ribose pocket, along with the hinge and hydrophobic region, based on ATP-kinase interactions. Herein, we report the discovery of a novel 4'-thionucleoside template as a multi-kinase inhibitor with potent anticancer activity. The in vitro evaluation revealed a lead 1g (7-acetylene-7-deaza-4'-thioadenosine) with potent anticancer activity, and marked inhibition of TRKA, CK1δ, and DYRK1A/1B kinases in the kinome scan assay. We believe that these findings will pave the way for developing anticancer drugs.

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