Discovery of Marinopyrrole A (Maritoclax) as a Selective Mcl-1 Antagonist that Overcomes ABT-737 Resistance by Binding to and Targeting Mcl-1 for Proteasomal Degradation

Kenichiro Doi,Rongshi Li,Shen-Shu Sung,Hongwei Wu,Yan Liu,Wanda Manieri,Gowdahalli Krishnegowda,Andy Awwad,Alden Dewey,Xin Liu,Shantu Amin,Chunwei Cheng,Yong Qin,Ernst Schonbrunn,Gary Daughdrill,Thomas P Loughran,Said Sebti,Hong-Gang Wang

doi:10.1074/jbc.m111.334532

Abstract

The anti-apoptotic Bcl-2 family of proteins, including Bcl-2, Bcl-X(L) and Mcl-1, are well-validated drug targets for cancer treatment. Several small molecules have been designed to interfere with Bcl-2 and its fellow pro-survival family members. While ABT-737 and its orally active analog ABT-263 are the most potent and specific inhibitors to date that bind Bcl-2 and Bcl-X(L) with high affinity but have a much lower affinity for Mcl-1, they are not very effective as single agents in certain cancer types because of elevated levels of Mcl-1. Accordingly, compounds that specifically target Mcl-1 may overcome this resistance. In this study, we identified and characterized the natural product marinopyrrole A as a novel Mcl-1-specific inhibitor and named it maritoclax. We found that maritoclax binds to Mcl-1, but not Bcl-X(L), and is able to disrupt the interaction between Bim and Mcl-1. Moreover, maritoclax induces Mcl-1 degradation via the proteasome system, which is associated with the pro-apoptotic activity of maritoclax. Importantly, maritoclax selectively kills Mcl-1-dependent, but not Bcl-2- or Bcl-X(L)-dependent, leukemia cells and markedly enhances the efficacy of ABT-737 against hematologic malignancies, including K562, Raji, and multidrug-resistant HL60/VCR, by ∼60- to 2000-fold at 1-2 μM. Taken together, these results suggest that maritoclax represents a new class of Mcl-1 inhibitors, which antagonizes Mcl-1 and overcomes ABT-737 resistance by targeting Mcl-1 for degradation.

Highlights

There is an urgent need to develop small molecule Mcl-1-specific inhibitors for the treatment of Mcl-1-dependent ABT-737/263-resistant cancers
We have identified the natural product marinopyrrole A as a novel Mcl-1-specific inhibitor and named it maritoclax
It has been demonstrated that ERK-mediated phosphorylation of Mcl-1 at Thr163 prolongs the half-life of Mcl-1 [42], whereas phosphorylation of Ser159 by GSK3 leads to increased ubiquitination and degradation of Mcl-1 [33]

Summary

Background

There is an urgent need to develop small molecule Mcl-1-specific inhibitors for the treatment of Mcl-1-dependent ABT-737/263-resistant cancers. Bad binds and antagonizes Bcl-2 and Bcl-XL but not Mcl-1, whereas Noxa binds and antagonizes Mcl-1 but not Bcl-2 and Bcl-XL This observation suggests that the BH3-only proteins provide a fine control of MOMP in a Bax/Bak-dependent manner and opportunities to design specific inhibitors for each of the anti-apoptotic Bcl-2 family members. The most potent and selective small-molecule Bcl-2 inhibitors are ABT-737 and its orally active analog ABT-263, which inhibit Bcl-2 and Bcl-XL at subnanomolar concentrations but only weakly target Mcl-1 [10] These agents generally lack efficacy in cancers with elevated Mcl-1 and in many instances this resistance can be overcome by down-regulation of Mcl-1 (10 –16). This study is the first to identify a small-molecule Mcl-1-specific inhibitor that binds Mcl-1 and induces its degradation in human cancer cells

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION