Authors:

Nikki Leslie

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About Paper:

G-protein-coupled receptors (GPCRs) are the largest family of cell surface signaling receptors and are known to activate diverse signal transduction pathways. GPCR kinases (GRKs) regulate GPCR signaling through selective phosphorylation which promotes their desensitization and internalization, thus maintaining cellular homeostasis. Furthermore, GRKs in pathopsychological conditions can promote tumorigenesis and metastasis, with processes such as the transactivation of receptor tyrosine kinases (RTKs). The GRK family (GRK1-7) is classified based on structural and sequence similarity into three kinase subfamilies: visual (GRK1/7), GRK2-like (GRK2/3), and GRK4-like (GRK4/5/6). GRK5 is upregulated in metastatic cancers and is a promising cancer therapeutic target. We hypothesize that our novel GRK5 inhibitors will enable superior selectivity for GRK5 to enhance therapeutic outcomes. Sunitinib, an FDA-approved multitargeted RTK inhibitor, is used to treat patients with renal cell carcinoma and gastrointestinal stromal cancer. Previously, we have developed a class of highly selective inhibitors targeting GRK5 derived from Sunitinib and elucidated the structures of GRK5 bound to some of these compounds. Current progress focuses on testing them in Pancreatic Ductal Adenocarcinoma (PDAC) cell growth and migration in vitro assays. In parallel, we developed a new class of macrocyclic compounds derived from previously published GRK6 inhibitors. We collected X-ray diffraction data and resolved the structures of GRK5 bound to these new compounds, which will allow us to understand drug-target interactions and optimize compound potency and selectivity. Future work will be to test the macrocyclic compounds in cell growth and migration in vitro assays using PDAC cancer cell lines. Keywords: GRK; Cancer; Drug Development; GPCR; X-Ray Crystallography

Source:

Purdue University / 2024

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Co-authors:

Nikki Leslie