Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors

Waldschmidt, Helen V.; Homan, Kristoff T.; Cruz-Rodríguez, Osvaldo; Cato, Marilyn C.; Waninger-Saroni, Jessica; Larimore, Kelly M.; Cannavo, Alessandro; Song, Jianliang; Cheung, Joseph Y.; Kirchhoff, Paul D.; Koch, Walter J.; Tesmer, John J.  G.; Larsen, Scott D.

doi:10.1021/acs.jmedchem.5b02000

Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors

Journal Article · Wed Apr 13 00:00:00 EDT 2016 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.5b02000· OSTI ID:1255284

Waldschmidt, Helen V. ^[1]; Homan, Kristoff T. ^[1]; Cruz-Rodríguez, Osvaldo ^[1]; Cato, Marilyn C. ^[1]; Waninger-Saroni, Jessica ^[1]; Larimore, Kelly M. ^[1]; Cannavo, Alessandro ^[2]; Song, Jianliang ^[2]; Cheung, Joseph Y. ^[2]; Kirchhoff, Paul D. ^[1]; Koch, Walter J. ^[2]; Tesmer, John J. G. ^[1]; Larsen, Scott D. ^[1]

Univ. of Michigan, Ann Arbor, MI (United States)
Temple Univ., Philadelphia, PA (United States)

G protein-coupled receptors (GPCRs) are central to many physiological processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-associated coiled-coil kinase 1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystallized in the active site. Guided by its binding pose overlaid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This campaign produced several compounds possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compound, 12n (CCG-224406), had an IC₅₀ for GRK2 of 130 nM, >700-fold selectivity over other GRK subfamilies, and no detectable inhibition of ROCK1. In addition, four of the new inhibitors were crystallized with GRK2 to give molecular insights into the binding and kinase selectivity of this class of inhibitors.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: American Heart Association (AHA); Center for Discovery of New Medicines, University of Michigan; Michigan Economic Development Corporation and Michigan Technology Tri-Corridor Grant; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1255284

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 8 Vol. 59; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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