Abstract 5933: Identifying MC4R-targeted small molecule to investigate MC4R impact on cachexia progression

Abstract

Abstract Background: The melanocortin system participates in energy homeostasis and appetiteregulation. This metabolic system is primarily located in the central nervous system,specifically in the hypothalamus and brainstem region. Within the melanocortin system,there are five established melanocortin receptors (MCR). MCRs are g-protein-coupledreceptors (GPCRs) and when these receptors are activated, they can increase neuronexcitation, regulate neurotransmitter release, regulate synaptic input, and alterconnection and strength. When Melanocortin-4 Receptor (MC4R) plays a critical role inthe progression of multiple metabolic diseases including cachexia. Cachexia is definedas the reduction of fat and lean mass, which is caused not just by lack of appetite, but byinflammatory impact. Cachexia is a symptom seen in numerous chronic diseases fromcancer to mitochondrial dysfunction to autoimmune inflictions. This makes MC4R apotentially strong therapeutic target. Method: In-silico and high-throughput methods were used to identify small moleculesthat target and inhibit MC4R. For high-throughput screen, Hek293 cells withconstitutively active MC4R tagged with a nanoluciferase were used to identify molecules,specifically with inhibitory qualities. cAMP accumulation and β-arrestin recruitmentassay were used to determine the impact on MC4R functionality. Results: 4738 small molecules were screened using high-throughput methods. Using a60% cutoff, 21 small molecules were identified as potential MC4R inhibitors. 17 arecurrently under investigation to confirm high-throughput results and identify functionalimpact. Several of these molecules have shown promising potential in vitro and will likelymove forward into in vivo studies. Conclusion: This study identifies prospective small molecule inhibitors that targetMC4R and may be used as a probe to explore MC4R biology. Citation Format: Julia Stokes, Dhanir Taylor, Marie Foss, Benedikt Grau, Sanjay Malhotra. Identifying MC4R-targeted small molecule to investigate MC4R impact on cachexia progression [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(6_Suppl):Abstract nr 5933.