Induction of apoptosis and antitumor effects of a small molecule inhibitor of Bcl-2 and Bcl-xl, gossypol acetate, in multiple myeloma in vitro and in vivo

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H3:H4 tetramers in the cytoplasm. It may have a role in cancer metabolism by linking cytoplasmic production of acetyl-CoA to nuclear acetyl flux. This is because the HAT1 di-acetylation mark is not propagated in chromatin and instead is de-acetylated after nascent histone insertion into chromatin. Thus, HAT1 likely provides a nuclear source of free acetate that may be recycled to acetyl-CoA for nuclear acetylation reactions. Correspondingly, suppression of HAT1 protein expression impairs tumor growth. To ascertain whether targeting HAT1 is a viable anti-cancer treatment strategy we sought to identify small molecule inhibitors of HAT1. We developed a high-throughput HAT1 acetyl-click assay to facilitate drug discovery and enzymology. Screening of small molecules computationally predicted to bind the active site led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity by competing with acetyl-CoA binding. These hits were refined by synthesis and testing over 70 analogs, which yielded structure-activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl sidechain improved enzymatic potency and cellular growth suppression. These efforts resulted in a lead compound (JG-2016) that suppressed growth of human cancer cells lines in vitro and impaired tumor growth in vivo. This is the first report of a small molecule inhibitor of the HAT1 enzyme complex and represents a step towards targeting this pathway for cancer therapy.

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The Jak2 Small Molecule Inhibitor, G6, Reduces the Tumorigenic Potential of T98G Glioblastoma Cells In Vitro and In Vivo

PLoS ONE ◽

10.1371/journal.pone.0105568 ◽

2014 ◽

Vol 9 (8) ◽

pp. e105568 ◽

Cited By ~ 5

Author(s):

Rebekah Baskin ◽

Sung O. Park ◽

György M. Keserű ◽

Kirpal S. Bisht ◽

Heather L. Wamsley ◽

...

Keyword(s):

Small Molecule ◽

Small Molecule Inhibitor ◽

Glioblastoma Cells ◽

Molecule Inhibitor ◽

Tumorigenic Potential

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Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer

Science Advances ◽

10.1126/sciadv.aax2277 ◽

2019 ◽

Vol 5 (9) ◽

pp. eaax2277 ◽

Cited By ~ 12

Author(s):

Lei Wang ◽

Lixiao Zhang ◽

Li Li ◽

Jingsheng Jiang ◽

Zhen Zheng ◽

...

Keyword(s):

Colorectal Cancer ◽

Small Molecule ◽

Protein Interaction ◽

Small Molecule Inhibitor ◽

Protein Protein Interaction ◽

Molecule Inhibitor ◽

Dependent Cell ◽

Hsp90 Chaperone

Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein interaction (PPI) in colorectal cancer. DDO-5936 disrupted the Hsp90-Cdc37 PPI both in vitro and in vivo via binding to a previously unknown site on Hsp90 involving Glu47, one of the binding determinants for the Hsp90-Cdc37 PPI, leading to selective down-regulation of Hsp90 kinase clients in HCT116 cells. In addition, inhibition of Hsp90-Cdc37 complex formation by DDO-5936 resulted in a remarkable cyclin-dependent kinase 4 decrease and consequent inhibition of cell proliferation through Cdc37-dependent cell cycle arrest. Together, our results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy.

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