Design and synthesis of tricyclic cores for kinase inhibition

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Abstract

Interest in therapeutic kinase inhibitors continues to grow beyond success in oncology. To date, ATP-mimetic kinase inhibitors have focused primarily on monocyclic and bicyclic heterocyclic cores. We sought to expand on the repertoire of potential cores for kinase inhibition by exploring tricyclic variants of classical bicyclic hinge binding motifs such as pyrrolopyridine and pyrrolopyrazine. Herein we describe the syntheses of eight alternative tricyclic cores as well as in vitro screening results for representative kinases of potential therapeutic interest.

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Acknowledgments

The authors would like to thank Eric Dominguez, Lori Dowding, Silvia Kwak, Sara Murdock, Takazvida Nyaundi, Denise Perron, Jose-Andres Salmeron-Garcia and Carmen Szynal for their contributions in obtaining in vitro enzyme activity and cellular data. Additionally, we would also like to thank Matthew Kurnick and Lemma Kifle for acquiring the in vitro binding data.

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