PROJECT SUMMARY / ABSTRACT Cancer-induced skeletal muscle atrophy is a central and defining feature of the cancer cachexia syndrome, a highly prevalent condition that affects over 50% of patients with advanced cancer and over 500,000 patients per year in the U.S. In addition to being highly prevalent, cancer-induced skeletal muscle atrophy has devastating consequences for patients; it reduces physical function and quality of life, often complicates or precludes cancer treatment, and strongly predicts early mortality from cancer. Unfortunately, a pharmacologic therapy for cancer-induced muscle atrophy does not exist. Thus, cancer-induced skeletal muscle atrophy represents a highly significant unmet medical need with broad relevance to cancer patients. A major goal of Emmyon, Inc. is to discover and develop a pharmacologic therapy for cancer-induced skeletal muscle atrophy. To that end, we recently discovered a natural compound that significantly reduces cancer-induced muscle atrophy in five well-established and distinct in vivo mouse models of cancer. We then used that natural compound as a lead in medicinal chemistry program and discovered and patented a confidential and proprietary chemical derivative (EMMY1-06) that appears to be significantly more potent and more efficacious than the lead compound in at least two distinct mouse models of cancer-induced muscle atrophy. In this Phase II SBIR proposal, we seek to continue this exciting work by advancing the development of EMMY1-06 and related molecules as pharmaceuticals for cancer-induced skeletal muscle atrophy. Specifically, we will further investigate EMMY1-06's safety, efficacy, and mechanisms of action in several distinct and complementary mouse models of cancer-induced muscle atrophy that involve multiple tumor types, sexes, and ages; these studies will significantly advance EMMY1-06 towards clinical development and commercialization in SBIR Phase III. In parallel to our detailed studies of EMMY1-06, we will also design, synthesize, and characterize novel compounds that are structurally related to EMMY1-06, seeking to discover additional compounds with pharmacologic properties that are similar to or perhaps even better than those of EMMY1-06 in preclinical models of cancer-induced muscle atrophy. Together, these studies will rigorously advance the scientific understanding and commercial development of a highly promising new class of pharmaceutical agents. Through this work, we hope to ultimately discover and develop a new pharmacologic therapy that could broadly improve clinical outcomes for millions of patients who suffer from cancer.