The transcription factor MYC (c-MYC and MYCN) plays a key role in cancer but small molecule inhibitors of it have been elusive. A new series of PI3K inhibitors has been under investigation and through molecular modeling compounds have been designed to also inhibit the bromodomain protein BRD4. We used structure-based drug design to create a series of anticancer compounds based on a thieno-pyranone core that potently inhibit both the epigenetic regulator bromodomain protein BRD4 and the key nodal survival signaling kinase PI3K. Two lead dual PI3K/BRD4 inhibitors from our research are: pan-PI3K inhibitor SF2523 (PI3K alpha, beta, delta, gamma IC50 values in nM: 17, 214, 27, 232) inhibiting BRD4-1 and BRD4-2 (IC50 = 318 nM and 1660 nM), and delta-PI3K selective inhibitor SF2535 (PI3K alpha, beta, delta, gamma IC50 values in nM: 714, 1750, 27, 1170) inhibiting BRD4-1 and BRD4-2 (IC50 = 277 nM and 628 nM). Our results indicate that SF2523 blocks BRD4 binding to MYCN promoter PS1/PS2 using chromatin precipitation experiments. This approach provides for the first time access to inhibit the activity of MYC by enhancing its degradation (PI3K inhibition) and blocking MYC production via the inhibition of MYC transcription (BRD4 inhibition). Our studies demonstrate that SF2523 blocks M1-M2 transition and decreases levels of p-AKT, N-MYC in several neuroblastoma cell lines as well as in vivo simultaneous pharmacodynamic knockdown. Other in vivo studies show SF2523 blocks spontaneous metastasis and tumor growth. To date, SF2523 has demonstrated animal efficacy results without toxicity in the following 4 animal models: orthotopic pancreatic model, multiple myeloma model, renal cell carcinoma model, neuroblastoma xenograft model. The crystal structure of the dual PI3K/BRD4 inhibitor SF2523 with BRD4 has been determined providing key insights towards the design of more potent analogs. Our studies provide evidence that inhibition of PI3K-gamma and PI3K-delta by our thieno-pyranone chemotypes function as checkpoint inhibitors and enhance immune-therapeutics while BRD4 inhibition has been shown to block tumor-specific super-enhancers activating the innate and adaptive immune response providing a novel strategy to treat cancer. These dual inhibitors represent a new therapeutic approach inhibiting two key anticancer orthogonal mechanisms, BRD4 and PI3K, showing significant efficacy justifying further development efforts towards clinical evaluation.

Citation Format: Alok Singh, Shweta Joshi, Joseph R. Garlich, Guillermo Morales, Tatiana Kutateladze, Forest Andrews, Donald Durden. A novel dual epigenetic/kinase inhibitory platform: SF2523 and analogues as first-in-class PI3K/BRD4 inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-211.