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Abstract G protein-coupled receptor kinases (GRKs) regulate cell signaling by triggering receptor desensitization via phosphorylation on G protein-coupled receptors (GPCRs). There are seven human GRKs (GRK1−GRK7) where GRK5 and GRK6 are structurally similar. GRK5 is ubiquitous and required for cancer progression in various cancer types. Knock-down of GRK5 has been shown to suppress prostate cancer and non-small-cell lung cancer growth. GRK6 is highly abundant in immune cells and is overexpressed in multiple myeloma (MM). Knocking down GRK6 has been shown to cause apoptosis of MM cells. Therefore, targeting GRK5 or 6 is a potential chemotherapeutic strategy. Currently, we are developing a series of inhibitors for GRK5/6 based on a lead compound derived from sunitinib and utilizing Cys474 residue unique in GRK5/6 to enhance selectivity by covalent capture. We tested a series of novel inhibitor warheads to improve potency and selectivity without potentially toxic functional groups. So far, we have identified several inhibitors with low nanomolar IC50 for GRK5 and more than 100, 000-fold selectivity over GRK2, another closely related member expressed in the heart. I have developed a pipeline of X-ray crystallography of GRK5 available for soaking various ligands and have solved several structures of novel inhibitor-bound GRK5. The structure elucidated the binding mode of this new class of GRK5 inhibitors, where the core interacts with the adenine site, a fluorophenyl group stabilizes the P loop and density suggests in some cases covalent bond forming between the reversible covalent warhead and Cys474. Our ongoing studies focus on further compound optimizations based on SAR. Overall, the discovery of the inhibitors can significantly facilitate understanding and treatment and cancers. Citation Format: Yueyi Chen, Amol D. Sonawane, Rajesh Manda, Ranjith K. Gadi, Arun K. Ghosh, John J. Tesmer. Structural insights and rational design, optimization of highly potent and selective novel GRK5/6 inhibitors for cancer therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5772.
Chen et al. (Fri,) studied this question.