Maximal MYC control using dual PI-3K/BRD4 (kinase/epigenetic) inhibitors

DESCRIPTION provided by applicant There is an unmet need to inhibit the key cancer promoting transcription factor MYC MYC both cMYC and MYCN acts downstream of many cell receptor complexes and signal transduction pathways to activate genes that drive cancer cell growth and proliferation To date small molecule inhibitors of MYC have been elusive An innovative approach would be to indirectly orthogonally diminish the activity of MYC by enhancing its degradation using PI kinase PI K inhibitors combined with blocking transcription of the gene producing MYC using inhibitors of the bromodomain protein BRD While small molecule inhibitors or PI K and BRD are individually used in cancer clinical trials none has made it through development to FDA approval Although combination treatments are common in cancer there is an unmet need for every increasing combinations to inhibit multiple targets to maximize efficacy This becomes unfeasible due to prohibitive costs when combining expensive targeted therapies in addition to being a barrier to early clinical evaluation of such complex combinations of drugs While exploring a novel PI K inhibitor scaffold thienopyranone TP scaffold based on a chromone derivative we discovered that these compounds also can potently inhibit BRD preliminary results The chromone backbone is common to the inhibition of BOTH targets thus providing the opportunity to now explore the newly found BRD activity while maintaining potent PI K activity overall objective Consolidating the inhibition of PI K AND BRD to maximally inhibit MYC activity with one molecule would fill all the unmet needs stated above This proposal will evaluate this approach by achieving the following aims setting the stage for phase II efforts to optimize the expected dual inhibitor lead compound s to a clinical candidate Aim Task Determine structure activity relationship SAR for TP compounds for BRD inhibition Approach Synthesize TP compounds and determine their BRD and PI K inhibition profiles Aim Task Develop predictive computational BRD model for the in silico docking of designed compounds Approach Vary the molecular in silico fit parameters of the BRD model until docking predictions of a TP dataset correlates with actual BRD assay binding results creating a validated docking model Aim Task Determine effects on MYC and therapeutic index for dual BRD PI K inhibition Approach Determine MYC expression and activity levels and compare toxicity towards cancer cell lines versus normal cell lines when exposed to single BRD or PI K versus dual BRD PI K inhibition conditions The contribution of this research is it provides an effective mechanism to block MYC activity that drives cancer and will be significant because it will allow enhanced combination treatments of MYC dependent cancers such as CLL medulloblastoma and neuroblastoma This approach is innovative because it attacks a key cancer target using two orthogonal mechanisms with a single compound and it challenges the cost ignoring efficacy limiting mentality of one drug one target prevalent in cancer research in an area with no FDA approved treatments

PUBLIC HEALTH RELEVANCE The planned research is relevant to public health because data we and others have acquired shows that our proposed development of a potent new PI kinase BET dual inhibitor to target cancer cells dependent upon the Myc oncogene Moreover the proposal is designed to produce a platform technology for the development of dual small molecule inhibitors of PI K combined with inhibitors of other targets thereby having a broad impact on public health Thus the proposed research which will involve a close collaboration between academia and industry is relevant to the part of the NIHandapos s mission that pertains to the development of new therapeutics able to reduce the burden of human disability via improved treatment of adult and childhood cancer