Small molecules binding cyclin-dependent kinase inhibitor 1b(p27kip1)

Abstract

Various compounds and pharmaceutically acceptable salts thereof are provided capable of binding cyclin-dependent kinase inhibitor 1B. The compounds can have a structure according to Formula I or Formula II as detailed herein. The compounds can include SJ747, SJ749, SJ755, SJ757. Pharmaceutical formulations containing the compounds or pharmaceutically acceptable salts are also provided along with methods of use thereof. The formulations and methods can be useful for treating cancer. In some aspects, the cancer is associated with a mislocalization of the intrinsically disordered protein p27. In some aspects, the cancer is resistant to an anticancer therapy. The pharmaceutical formulation can therefore include a second active agent and / or can be given in combination with a second active agent such as a cancer therapeutic. In various aspects, methods of promoting reentry into the cell division cycle in a subject in need thereof using compounds and formulations described herein are also provided.

Description

[0001] Cross References to Related Applications [0002] This application requires the name "SMALL MOLECULES THAT BINDCYCLIN-DEPENDENT KINASE INHIBITOR 1B (P27KIP1)" submitted on March 13, 2019, and the serial number is Priority and benefit of co-pending US provisional application 62 / 817,924, the contents of which are hereby incorporated by reference in their entirety. [0003] Statement Regarding Research or Development Sponsored by the U.S. Federal Government [0004] This invention was made with government support under Grant Nos. DC015010 and DC013879 awarded by the National Institutes of Health, and Grant No. N00014-18V-2507 awarded by the U.S. Office of Naval Research. The US Government has certain rights in this invention. technical field [0005] The present invention generally relates to compounds targeting intrinsically disordered proteins. Background technique [0006] Proteins exhibiting intrinsically disordered regions (IDRs) are ubiquitous in the human prote...

AI Technical Summary

Problems solved by technology

IDPs are challenging targets because they exist as ensembles of structures, which can make standard rational drug design methods difficult because they require knowledge of the three-dimensional structure of the protein to be administered

Despite understanding their association with numerous diseases, limited attention has been paid to developing strategies to therapeutically target IDPs and proteins with IDRs (Heller, G.T. et al., Cell MolLife Sci, 2017, Vol. 74 No. 17: No. 3225 -3243), and are generally considered "non-druggable" (Dang, C.V. et al., Nat Rev Cancer, 2017, Vol. 17, No. 8: pp. 502-508)

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