INHIBITORS OF CELLULAR TRANSPORTERS FOR THE TREATMENT OF TNBC

INHIBITORS OF CELLULAR TRANSPORTERS FOR THE TREATMENT OF TNBC Abstract Triple Negative Breast CancerTNBCis defined by the receptor status of the cellsTNBC does not express estrogenprogesteroneor HerreceptorsIt is estimated thatmillion women worldwide are diagnosed with breast cancer each yearTNBC is the most deadly sub type of breast canceraccounting forof the breast cancer diagnoses andof breast cancer related deathsMedian survival forof the patients with TNBC isyearTNBC arises more frequently in women younger thanyears of ageparticularly of African American descentand those who possess the BRACmutationSeventy five percentof womenwho have breast cancer with the BRACmutationwill develop TNBCTNBC has poor clinical outcomes because it is highly metastaticresistant to chemotherapyand lacks effective treatment optionsNirogyone s approach is to develop small molecule MCTMCTdual inhibitors to shunt glycolysisblock metabolic symbiosisprevent metastasisand effectively treat TNBCA novel lead moleculeNGThas already been synthesizedand evaluated in in vitro and in vivo pilot experimentsPreliminary data demonstrates that NGTexhibits good potency against a TNBC cell linesMDA MBand MDA MBgood physicochemical propertiesreasonable mouse pharmacokinetic profileand modest in vivo efficacyNGTshowed no cytotoxicity even atM against several normal cell lines including muscle cells which are known to express MCTsIn this applicationwe propose to further characterize NGTand its optimized analogs by conducting the following AIMSDevelop analogs of NGTwith improved pharmacokinetic profile and potency by iterative synthesis and homology models of MCTand MCTto aid in the discovery of new improved lead compounds to increase in vivo efficacyExtend in vitro cytotoxicity studies to other TNBC cell linesEvaluate the in vivo efficacy of the optimized analog in a mouse xenograft model of MDA MBwhile establishing aD co culture systemThe proposed work will determine the feasibility of NGTor its optimized analog as a novel therapeutic agent to treat TNBCNext steps will be to evaluate an optimized analog in additional in vivo studiesorthotopic modelsPDX modelsdose responsedosing regimentoxicology assessmentetcas determined by results from AIMSandin order to nominate a pre clinical candidateThis will be a part of Phase II application