A Novel STAT3 Inhibitor Targeting its DNA-Binding Site for Drug Development

DESCRIPTION provided by applicant Cancer is a major public health problem and a leading cause of mortality claiming more than half million lives every year in the US While major progresses have been made in developing targeted anticancer therapeutics many cancers such as lung cancers have no effective treatments Unfortunately many ideal oncogenic targets including transcription factors for these cancers are considered andquot undruggableandquot and simply avoided for discovery of targeted therapeutics STAT a transcription factor in the Janus kinase JAK STAT signaling pathway is constitutively activated in most human cancers including lung and breast cancers and has been shown to drive tumorigenesis Thus STAT is a sought after target for discovery of anticancer drugs Indeed targeting the SH domain of STAT for drug discovery has been attempted However the clinical efficacy of these inhibitors is limited and some are poorly tolerated in humans On the other hand targeting the DBS of STAT has not been in the main stream of research due to the taboo that the DNA binding site DBS is andquot undruggableandquot Using an improved in silico screening approach a STAT selective small molecule inhibitor inS targeting the DBS of STAT was recently identified which effectively inhibits cancer cell proliferation migration and invasion These findings suggest tha the DBS of STAT may be druggable challenging the prevailing dogma of DBS as an andquot undruggableandquot site and may promise a potential therapeutics for the difficult to treat human cancers The long term objective of QRKanswer LLC an Indiana based small business is to investigate inhibitors targeting the DBS of STAT for potential drug development In this Phase I STTR application QRKanswer and its research partners at Indiana University School of Medicine plan to investigate the active analogues of inS and newly synthesized new composition of matters to identify lead inhibitors for potential anticancer drug development To this end two aims will be accomplished to evaluate the active inS analogues and new composition of matters using in vitro cell based assays and evaluate the lead analogues for preclinical pharmacokinetics toxicity and efficacy At the conclusion of this study QRKanswer will have a lead inhibitor targeting the DBS of STAT with preclinical data for Phase II study in which QRKanswer will further investigate the lead compound for filing IND and potentially testing safety in phase I clinical trial of solid tumors such as breast and lung cancers with estimated and new cases in respectively The successful outcome will help QRKanswer gain entry into this market PUBLIC HEALTH RELEVANCE Human cancer is a major public health issue claiming more than half million lives in the US alone In this Phase I STTR application QRKanswer an Indiana based small business and its research partners at Indiana University School of Medicine plans to develop novel inhibitors targeting STAT molecule which is constitutively activated in human cancers by challenging the prevailing dogma of andquot undruggableandquot DNA binding sites of transcription factors The outcome is expected to have significant impact on treatment of human cancers and on drug discovery targeting the andquot undruggableandquot oncogenic targets