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GRK5 has become an important drug development target against heart failure and cancer. GRK6, a close homolog of GRK5, is considered as a possible therapeutic target for multiple myeloma. A series of drug\u2010like GRK5 inhibitors that form noncovalent interactions in the GRK5 active site are designed. In the design of these molecules, pyrroloindoline basic scaffold of sunitinib, an FDA\u2010approved drug, is utilized and various <jats:italic>N<\/jats:italic>\u2010heterocyclic carboxamides in the active site are incorporated. Several inhibitors exhibit low nanomolar GRK5 inhibitory activity and high selectivity over GRK2. Several compounds also display very potent activity and selectivity for GRK6. A high\u2010resolution X\u2010ray crystal structure of one of these small molecule inhibitors in complex with GRK5 is determined. The structure provides important molecular insights regarding ligand\u2010binding site interactions, GRK5 inhibition, and selectivity against GRK2.<\/jats:p>","DOI":"10.1002\/cmdc.202500257","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T14:30:41Z","timestamp":1747665041000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Potent, Selective, and Drug\u2010Like G Protein\u2010Coupled Receptor Kinase 5 and 6 Inhibitors: Design, Synthesis, and X\u2010Ray Structural Studies"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2472-1841","authenticated-orcid":false,"given":"Arun K.","family":"Ghosh","sequence":"first","affiliation":[{"name":"Department of Chemistry Purdue University  West Lafayette IN 47907 USA"},{"name":"Department of Medicinal Chemistry and Molecular Pharmacology Purdue University  West Lafayette IN 47907 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ranjith Kumar","family":"Gadi","sequence":"additional","affiliation":[{"name":"Department of Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology Purdue University  West Lafayette IN 47907 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandali Piladuwa","family":"Gamage","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Purdue University  West Lafayette IN 47907 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn P.","family":"McCauley","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Purdue University  West Lafayette IN 47907 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J. 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