Abstract 1805: Characterization of pyoluteorin derivatives as Mcl-1 antagonists
Authors: Kenichiro Doi, Krishne Gowda, Qiang Liu, Shen-Shu Sung, Jyh Ming Lin, Shantu Amin, Thomas P. Loughran, Hong-Gang Wang
Journal: Cancer Research (2014)

Abstract The evasion of apoptosis is considered to be a hallmark of cancers and a cause of resistance to anti-cancer therapies. Consistently, aberrant overexpression of anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-xL, Mcl-1) is associated with tumorigenesis and increased resistance to chemotherapy in multiple malignancies. To date, several small-molecule Bcl-2 inhibitors that bind the BH3-binding pocket of the protein have entered clinical trials. These BH3 mimetics are known to induce apoptosis by disrupting the interactions between pro- and anti-apoptotic Bcl-2 family proteins. The most well characterized selective agents are the Bcl-2 inhibitor ABT-737 and its orally active analog ABT-263 which inhibit Bcl-2 and Bcl-XL but not Mcl-1. Consequently, cancers with elevated Mcl-1 do not respond to these drugs. Moreover, Mcl-1 is frequently upregulated in cancer cells and compensates for the inhibition of Bcl-2 function by ABT-737, thereby mediating resistance to the drug. Thus, there is an urgent need to develop Mcl-1-specific inhibitors for the treatment of Mcl-1-dependent human cancers. We have recently identified and characterized the natural product marinopyrrole A (maritoclax) as a novel Mcl-1 inhibitor, which induces apoptosis by targeting Mcl-1 for proteasomal degradation without significant effects on mRNA levels. To determine the pharmacophore of maritoclax, we systematically altered or removed portions of the molecule to identify regions essential for inhibition of Mcl-1 and induction of apoptosis. To date, we synthesized over 40 derivatives of maritoclax and evaluated their inhibitory actions toward Mcl-1 and cytotoxicity in cell lines of human hematological malignancies. As a result, we have identified several pharmacophore sites in maritoclax that are required for biological activity and two pyoluteorin derivatives, KS04 and KS18, which bind to a similar site(s) in Mcl-1 as maritoclax, as determined by NMR titration experiments. Like maritoclax, KS04 or KS18 markedly reduced the half-life of Mcl-1 protein, induced apoptosis selectively in Mcl-1-dependent but not Bcl-2-dependent K562 cells, and acted synergistically with ABT-737 to enhance apoptosis in ABT-737 resistant HL60 cells. Moreover, the combination treatment of KS18 (10 mg/kg/d) and ABT-737 (20 mg/kg/d) significantly suppressed the growth of ABT-737-resistant HL60 xenografts in nude mice. Thus, further studies are warranted to develop pyoluteorin derivatives as a novel class of Mcl-1 inhibitors. Citation Format: Kenichiro Doi, Krishne Gowda, Qiang Liu, Shen-Shu Sung, Jyh Ming Lin, Shantu Amin, Thomas P. Loughran, Hong-Gang Wang. Characterization of pyoluteorin derivatives as Mcl-1 antagonists. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1805. doi:10.1158/1538-7445.AM2014-1805