Development of the first-in-class novel dual PI-3K/BRD4 inhibitor SF2523

There is an unmet need to inhibit the key cancer promoting transcription factor MYCboth c MYC and MYCNthat act downstream of many cell receptors and signal transcription pathways to activate genes for cancer cell resistance and tumor growthTo datesmall molecule inhibitors of MYC have remained elusiveIn our Phase I STTRCAwe developed a lead compoundSFwhich displays potent orthogonal inhibitory activity against MYC by blocking PIkinasePIKand the highly dominant regulator of epigenetic machineryBRDThe objective of this application will be to develop SFthrough advanced preclinical studies for therapeutic application in this Phase II STTR proposalThe transcription factorMYCc MYC and MYCNplays a key role in cancer growthproliferationsurvivaland it is overexpressed in a subgroup of most human cancers resulting in resistance to PIK and other signaling pathway inhibitorsBoth MYC and PIK are well established onco proteins that are confirmed drivers in a large number of tumor typesMoreoverBRDis rapidly emerging as a dominant epigenetic regulator of the transcriptome and of cancer cell resistance to kinase inhibitionThereforethere is general consensus in the cancer biology arena that inhibition of BRDand or MYC should prove beneficial in multiple cancers where MYC is an established regulator of tumor cell transformation and resistanceOur innovative approach centers on our central hypothesis that a dual PIK BRDinhibitorSFwill potently inhibit MYC activity by enhancing its degradation via PIK inhibition AND blocking MYC transcriptional activity via BRDinhibitionOur Phase I STTR Specific Aims successfully solved the crystal structure of SFin the active site of BRDand determine the structure activity relationships around dual PIK BRDinhibitors designed by validated molecular modeling studies and demonstrated the safety of our dual targeting single inhibitor versus the accumulated toxicity of using two separate inhibitorsOur successful Phase I studies set the stage for our selection of SFas the candidate for preclinical development to treat PIK MYC dependent malignancies in Phase I trials as a clinical development strategyThe significance of this Phase II proposal is that it will advance SFthrough preclinical development and validate this novel dual PIK BRDinhibitor as a drug candidate against PIK MYC driven malignancies with high mortality rates e ghepatocellular carcinomaHCCand squamous cell carcinoma of the head neckSCCHNand obtain a back up candidate by further evaluation of SFanalogs found from Phase I SAR studiesMoreoverour aims in Phase II will identify PIK and MYC tumor signatures and a companion diagnostic approach which will define sensitivity to SFas we move toward FDA registration and commercialization of thisfirst in classdual PIK BRDinhibitor chemotype in cancer therapeutics