Identification of first in class small molecule GFRAL blockers for the prevention and reversal of Cancer Anorexia-Cachexia

鉴定用于预防和逆转癌症厌食-恶病质的一流小分子 GFRAL 阻滞剂

• 批准号: 10091640
• 负责人: Margaret Jackson
• 金额: $ 5.5万
• 依托单位: BYOMASS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091640
• 关键词: Address; Advanced Malignant Neoplasm; Affect; Agonist; Anorexia; Antibodies; Binding; Biological; Biological Assay; Body Weight decreased; Brain; Brain Stem; Cachexia; Cancer Etiology; Cancer Model; Cancer Patient; Catabolism; Chemicals; Chemistry; Clinical; Clinical Trials; Development; Disease; Diversity Library; Dose; Drug Kinetics; Exhibits; Family; Fatty acid glycerol esters; Formulation; G-Protein-Coupled Receptors; GDF15 gene; GDNF receptors; Goals; Grant; Human; In Vitro; Investigational Drugs; Knock-in Mouse; Knowledge; Lead; Libraries; Life; Ligands; Luciferases; Malignant Neoplasms; Mediating; Medical; Metabolism; Modeling; Mus; Operative Surgical Procedures; Oral; Outcome; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmacology; Pharmacotherapy; Phase; Plasma; Positioning Attribute; Prevention; Primates; Probability; Radiation therapy; Rattus; Reporting; Risk; Rivers; Route; Running; Safety; Series; Skeletal Muscle; Structure; Symptoms; Testing; Time; TimeLine; Transfection; Tumor Burden; Tumor-Derived; Xenograft Model; analog; appetite loss; base; cancer anorexia; cancer cachexia; cancer therapy; chemotherapy; clinical candidate; computational chemistry; cost; cytokine; design; glial cell-line derived neurotrophic factor; high throughput screening; in silico; in vivo; in vivo Model; increased appetite; innovation; insight; lead optimization; mortality; muscle form; novel; patient stratification; pre-clinical; precision medicine; prevent; receptor; receptor binding; screening; small molecule; success; treatment duration; virtual; virtual screening

Project Summary The goal of the project is to identify for the first time, a brain-penetrant small molecule antagonist against Glial cell line-derived neurotrophic factor Family Receptor α-Like (GFRAL) for the prevention and reversal of cancer anorexia-cachexia. Anorexia-cachexia is a debilitating, life threatening disease, associated with pronounced loss of appetite, skeletal muscle and fat mass. Cancer anorexia-cachexia constitutes a major unmet medical need, as 80% of patients with advanced cancers exhibit cachexia and 20% of cancer-related mortalities are derived from cachexia rather than direct tumor burden. Patients are less tolerant to radiotherapy, chemotherapy, pharmacotherapy and surgery. As a result, patients receive lower doses, reduced duration of treatment or are not eligible for treatment, indirectly decreasing survival. There is currently no approved treatment for anorexia-cachexia thus representing a high unmet medical need. The etiology of cancer anorexia-cachexia is attributed to abnormal metabolism, induced by tumor- derived cytokines. Precachectic and cachectic patients have elevated levels of Growth Differentiation Factor-15 (GDF-15) which is correlated with poor survival. GDF-15 has emerged as critical factor mediating anorexia-cachexia. Preclinically, GDF-15 causes anorexia in mice, rats and primates while blocking endogenous GDF-15 in cancer cachexia models, prevents and reverses anorexia-cachexia with an impressive 100% survival. Recently, it has been identified that GDF-15 mediates its effects via GFRAL located within the brainstem. Blocking the effect of GDF-15 via GFRAL with a small molecule versus a biologic offers the best opportunity to access the brain and achieve sufficient concentrations to block >90% of GFRAL. BYOMass is in a unique position for success in identifying druggable small molecule antagonists facilitated by our knowledge of crucial GDF-15 and GFRAL binding regions. A key advantage of a GFRAL antagonist versus other mechanisms tested to date in clinical trials, is that for the first-time a.) cachexia can be cured rather than address symptoms of cachexia and b.) a precision medicine approach can be used to identify patients based on their plasma GDF-15 levels to increase efficacy and the number of responders. A successful outcome of Phase 1 will be hit identification from 1-2 lead chemical series that reverses cancer cachexia in mice. Pending a Phase 2 grant, Phase 1 leads will be optimized to deliver a clinical candidate for Investigational New Drug enabling studies. The once daily, oral candidate will block >90% GFRAL in cancer patients with elevated levels of GDF-15 (<1 ng/mL). Blocking GFRAL will increase appetite, decrease catabolism and increase muscle mass, to enable optimal anti-cancer therapy and increase survival.

项目总结