Abstract 6913: Discovery of GSC000580, a novel oral small molecule of MC4R antagonist for treatment of cancer-related body mass loss

Abstract Melanocortin 4 Receptor (MC4R) is heavily involved in appetite regulation, body mass and energy homeostasis. MC4R is a GPCR class A receptor that belongs to the melanocortin receptor family. When leptin binds to the receptor, POMC neurons release POMC, which is cleaved to form α-MSH, followed by activating MC4R to result in loss of appetite and weight loss. AGRP released from AGRP neurons inhibits MC4R signaling, which promotes appetite and increases body weight. Weight gain in MC4R KO mice is gene dose dependent. MC4R GOF mutations in human2 are associated with low BMI and LOF mutations are associated with obesity. Agonists of MC4R for treating POMC, leptin receptor and other genetic defects resulting in hereditary obesity, have been approved by the FDA . Antagonists of MC4R are expected to be developed for weight-related disorders like cancer anorexia and other types of anorexia. 27%-58% of patients with advanced cancer have loss of appetite, 33%-75% have anorexia, which significantly increased the risk of postoperative complications and mortality. Current progestogen drugs couldn’t offer adequate efficacy and favorable safety. MC4R antagonists with oral convenience may have the potential to recover or increase the appetite and body weight of patients with cancer-related anorexia, thereby improving their quality of life, further promoting the outcome of tumor treatment, and even improving OS. Currently, two MC4R antagonists have progressed to phase I clinical study. TCMCB07, an MC4R antagonist peptide, has shown efficacy in various cancer anorexia rat models but its use is limited due to the requirement for intravenous administration. PF-07258669 is an oral small molecule MC4R antagonist with efficacy in an aged rat model of anorexia. Here we report the discovery of GSC000580, a novel, highly potent and selective MC4R antagonist that exhibits strong in-vitro activity and has been shown to induce increased food intake and body mass gain in two animal models of anorexia. In vitro, GSC000580 could bind to MC4R receptor with less than 1nM potency with high (500∼1000 fold) selectivity across the melanocortin receptor family and potently blocking cAMP production with less than 1nM potency in cellular functional assay. In vivo, GSC000580 demonstrated dose-dependent significant increase of body weight gain and food intake in cisplatin-induced and aging-related anorexia rat models. GSC000580 has a favorable ADME and PK profile in rodents, dogs and NHPs, along with an acceptable safety profile. Additionally, GSC000580 exhibits the ability of brain penetration, with a brain-to-plasma ratio (b/p) of 0.17. GSC000580 demonstrates promise as a potential clinical treatment for cancer-related body mass loss. Citation Format: Meng Liu, Sheng Zhao, Biao Lu, Yuanfeng Xia, Fanglong Yang. Discovery of GSC000580, a novel oral small molecule of MC4R antagonist for treatment of cancer-related body mass loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6913.