Abstract 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. It has recently been shown by others that PI3K inhibitors can help degrade the MYC protein. It has also been shown by others that inhibitors of the bromodomain protein BRD4 serve to block the transcription of MYC. Our innovative approach is to indirectly orthogonally diminish the activity of MYC by enhancing its degradation using PI3 kinase (PI3K) inhibitors combined with blocking transcription of the gene producing MYC using inhibitors of the bromodomain protein BRD4. While small molecule inhibitors or PI3K and BRD4 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 ever 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-3K inhibitor scaffold (TP Scaffold) based on a chromone derivative we discovered that these compounds also can potently inhibit BRD4. The chromone backbone is common to the inhibition of BOTH targets thus providing the opportunity to now explore the BRD4 inhibitory activity while maintaining potent PI3K activity. Consolidating the inhibition of PI3K AND BRD4 to maximally inhibit MYC activity with one molecule would fill all the unmet needs stated above. We have identified a lead compound, SF2523 that inhibits BRD4 (BRD4-1 IC50 241 nM, BRD4-2 IC50 1550 nM) and also is a pan-PI3K inhibitor (alpha, beta, delta, gamma IC50 34, 214, 960, and 158 nM respectively). We have demonstrated suitable ADME and PK properties for SF2523. The following preclinical results will be presented: a) Western blots demonstrating dual pathway inhibition; b) in vitro studies proving decreased MYC levels; c) antiproliferation data including patient derived cancer cells; d) antiangiogenic activity; e) induction of apoptosis and mechanisms thereof. Additionally, we will present data showing safety and efficacy of the dual PI3K/BRD4 inhibitor SF2523 in animal efficacy models including an orthotopic pancreatic model and Lewis Lung Carcinoma mouse model. In addition to the PI3K/BRD4 inhibitor our recent results with designed dual inhibitors within a single molecule aimed at PI3K/MEK, PI3K/HDAC, and other critical combinations will be presented. Our approach challenges the current dogma in the PI3K inhibitor field because it attacks a key cancer target using two orthogonal mechanisms within a single compound as well as challenges the cost-ignoring efficacy-limiting mentality of one-drug one-target prevalent in cancer research in an area with no FDA approved treatments. The results highlight the development of one of the first nanomolar potent dual PI-3K/BET bromodomain inhibitors for clinical development against PI-3K and epigenetic targets in the cancer cell. Citation Format: Alok R. Singh, Shweta Joshi, Joseph R. Garlich, Guillermo A. Morales, Donald Lee Durden. Dual PI3K/BRD4 (kinase/epigenetic) inhibitors for maximal MYC control in cancer therapeutics. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A27.