Augmenting the Anti-Leukemic Activity of the BCL-2 Inhibitor Venetoclax Through Its Transformation Into...

Motivated by the anti-leukemic synergy between histone deacetylase (HDAC) inhibitors and the FDA-approved BCL-2 inhibitor venetoclax, coupled with our interests in polypharmacology, we sought to bolster the anti-leukemic efficacy of the clinical drug by grafting HDAC1-selective or HDAC6-selective inhibitor motifs onto a solvent-accessible domain of venetoclax. We discovered multiple polypharmacological agents that both retained the potent BCL-2 inhibitory activity of venetoclax and effectively inhibited either HDAC1 or HDAC6 with excellent (up to 80-fold) selectivities for the desired HDAC isoform. In addition, relative to parental venetoclax, two of our lead compounds, BD-4-213 and AMC-4-154, exhibited superior activities against the acute myeloid leukemia cell line MV4;11 and an MV4;11 cell line engineered to overexpress BCL-2. Annexin-V assay results confirmed an on-target mechanism of apoptosis for these novel chimeric molecules. Efforts to further boost the HDAC1 or HDAC6 binding affinities and/or selectivities proved unsuccessful due to synthetic chemistry challenges and solubility problems, which may underscore the difficulties of polypharmacology approaches involving a large inhibitor, such as venetoclax.