Development of novel drugs to treat obesity

DESCRIPTION provided by applicant Obesity is a global issue Life threatening medical disorders associated with obesity include cardiovascular disease type diabetes and likely certain types of cancer these would be minimized if obesity could be better controlled In addition healthcare costs would be increasingly manageable in proportion to the reduction in obesity To supplement diet and exercise based measures to control obesity various drugs have been developed Most currently approved drugs such as lorcaserin Belviq and phentermine topiramate Qsymia rely on appetite suppression and subsequent reduced food intake while another orlistat marketed as Xenical and Alli works by reducing fat absorption In addition to being limited to populations of susceptible patients weight loss drugs are compromised by side effects often cardiovascular or psychiatric Thus additional novel therapeutics are being sought to combat obesity focusing on molecular mechanisms for example ubiquitylation deubiquitylation that can be affected pharmacologically to halt or reverse accumulation of excess fat Ubiquitin conjugating enzymes known as E ligases are a very large family of enzymes many of which have been linked genetically and or biochemically to various pathologies One ligase HRD is associated with adipose tissue knockout or knockdown of this ligase in mice leads to a large reduction in white adipose and weight loss Its ubiquitylation target appears to be PCG a transcriptional co activator involve in fatty acid metabolism and mitochondrial biogenesis It is therefore proposed here to develop small molecule inhibitors of HRD for treatment of obesity To accomplish this assays that have been used successfully at Progenra to discover molecules that are active against other physiologically relevant E ligases will be adapted to screen for novel HRD inhibitors for characterization and development as therapeutic agents for obesity Selected hits from the screen of Progenraandapos s small molecule collection will be evaluated for predicted physiological activity in cellular models based on PCG associated cell markers developed by Progenraandapos s collaborator Professor Toshihiro Nakajima of Tokyo Medical University In Phase II selected molecules with acceptable chemical properties and cell based activity will be put into pre clinical development for anti obesity therapy PUBLIC HEALTH RELEVANCE To improve the general health and quality of life of individuals and to contain healthcare costs it is desirable to find an effective treatment for obesity Curren anti obesity drugs are not ideal as they are of limited applicability and can produce dangerous side effects A novel target enzyme from the ubiquitin pathway HRD has been linked genetically to fat accumulation and weight gain so inhibitors of this enzyme will be identified and developed to treat obesity