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

  • J Biol Chem. 2012 Mar 23;287(13):10224-10235. doi: 10.1074/jbc.M111.334532.
Kenichiro Doi  1 ,  Rongshi Li  2 ,  Shen-Shu Sung  1 ,  Hongwei Wu  3 ,  Yan Liu  2 ,  Wanda Manieri  2 ,  Gowdahalli Krishnegowda  1 ,  Andy Awwad  4 ,  Alden Dewey  4 ,  Xin Liu  4 ,  Shantu Amin  5 ,  Chunwei Cheng  6 ,  Yong Qin  6 ,  Ernst Schonbrunn  2 ,  Gary Daughdrill  3 ,  Thomas P Loughran Jr  4 ,  Said Sebti  2 ,  Hong-Gang Wang  7
Affiliations
  • 1. Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
  • 2. Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612.
  • 3. Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida 33612, and.
  • 4. Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
  • 5. Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
  • 6. West China School of Pharmacy, Sichuan University, Chengdu, 610041, P. R. China.
  • 7. Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033,. Electronic address: [email protected].
PMID: 22311987 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.

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