• Inhibition of Anti-Apoptotic Protein MCL-1 and Epigenetic Reader BRD4 with Small Molecule Inhibitors: Structure-Based Drug Design and Polypharmacology

      Chen, Lijia; Fletcher, Steven; 0000-0002-5721-5091 (2016)
      One of the hallmarks of cancer is the evasion of programmed cell death. Programmed cell death is strictly regulated by the intrinsic apoptosis pathway, in which BCL-2 anti/pro-apoptotic proteins play vital roles. In normal cells, the delicate balance between anti-apoptotic BCL-2 proteins and their functional sequester: pro-apoptotic proteins, is precisely maintained to ensure the execution of cell death or cell proliferation. However, the apoptotic pathway is often dysregulated in cancer cells, demonstrated by the frequent observed over-expression of anti-apoptotic protein(s), such as BCL-2, BCL-xL and MCL-1. Therefore, targeted inhibition of BCL-2 anti-apoptotic proteins using small molecule inhibitors has been extensively researched to restore apoptosis and kill cancer cells. A decade of research is rewarded by the recent approval of the BCL-2 selective inhibitor Venetoclax as a second line therapy for chronic lymphocytic leukemia (CLL) patients. Nonetheless, due to the heterogenetic nature of cancers, inhibitors targeting other anti-apoptotic BCL-2 proteins should also be developed not only for different cancer types, but also for the potential resistance generated by MCL-1 up-regulation after BCL-2 inhibition. To date, numerous studies are currently ongoing to discover small molecule inhibitors targeting different anti-apoptotic BCL-2 proteins, primarily MCL-1 and/or BCL-xL, in order to provide insight to dissect these proteins' biological functions, and potentially yield various tool compounds as clinical candidates. Utilizing structure-based drug design strategy, we have designed and synthesized two distinct scaffolds: tetrahydroquinoline (THQ) and salicylate as MCL-1 inhibitors. SAR analysis has been conducted based on their biochemical binding affinities to facilitate the understanding of binding pocket properties. In vitro cell growth inhibition was also evaluated to estimate their potency at cellular level. Another survival mechanism of cancer is through the dysregulation of post-translational modifications, such as aberrant acetylation of histone lysine residues, which abnormally turn on the transcription and expression of oncogenes. Particularly, the bromodomain BRD4 protein is heavily involved in this process as an epigenetic reader to recognize the acetylated lysine residues on histone and regulate the transcription of several oncogenes including c-MYC and BCL-2. Therefore, inhibition of BRD4 may serve as an indirect method to modulate the level of c-MYC and BCL-2 oncoprotein in cancers. Recently, a PLK1 inhibitor BI-2536 was reported as a potent BRD4 inhibitor. The dual inhibition by a single drug molecule might provide the platform for a polypharmacological strategy to treat various cancers. With the guidance of structure-based drug design, we have synthesized and evaluated an SAR library of BI-2536 to dissect their PLK1 and BRD4 inhibition profiles. The fine-tuning modifications of functional groups on BI-2536 furnished both selective BRD4 inhibitors and stronger dual PLK1/BRD4 inhibitors.