Hematological malignancies are complex, multifactorial diseases that often require treatments which act through several different mechanisms. The BCL-2 family of proteins, which comprise of pro- and anti-apoptotic proteins, are regulators of apoptosis. In many cancers, antiapoptotic proteins, such as BCL-2, MCL-1, and BCL-xl, are overexpressed, sequestering their proapoptotic counterparts, thereby allowing the malignant cells to evade cell death; therefore, these antiapoptotic proteins are a common target for a variety of cancer therapeutics. Venetoclax is a BCL-2 selective inhibitor, which has shown efficacy in a wide range of hematological malignancies as well as other solid tumor cancers. Although venetoclax has received FDA approval, the median survival (in combination with hypomethylating agents) is only 18 months owing to the development of resistance, which manifests through BCL-2 mutations as well as over-expression of MCL-1. It was recently reported that the combination of venetoclax and histone deacetylase (HDAC) inhibitors elicited a synergistic effect in several cancers, which is due, in part, to the downregulation of BCL-2 and the upregulation of pro-apoptotic BCL-2 proteins. Accordingly, we have embarked on the development of novel BCL-2/HDAC dual inhibitors through the addition of zinc binding groups – a crucial component to the archetypal HDAC inhibitor pharmacophore – to venetoclax. There are several advantages to such a “polypharmacologic” approach, as opposed to the corresponding combination of drugs, i.e. polypharmacy, including the potential for increased therapeutic effect due to the simultaneous presence of both pharmacophores in malignant tissues. Though there are four FDA-approved HDAC inhibitors, these are all pan-inhibitors and are associated with considerable toxicity. It is generally believed that one strategy to mitigate these side effects is through the development of selective HDAC inhibitors. HDAC1 and HDAC6 have been implicated in a wide range of cancers. Therefore, we have designed and synthesized dual BCL-2/HDAC inhibitors to target HDAC1, as well as other dual inhibitors to target HDAC6. It is hypothesized that our polypharmacological approach will be comparable with the corresponding polypharmacy approach in cells but superior in vivo; our progress will be presented.

Polypharmacological BCL-2/HDAC dual inhibitor strategy to mitigate MCL-1 upregulation in venetoclax resistance

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