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.
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.
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
Kenichiro
K
Doi
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612.
Rongshi
R
Li
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
Shen-Shu
SS
Sung
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida 33612, and.
Hongwei
H
Wu
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612.
Yan
Y
Liu
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612.
Wanda
W
Manieri
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
Gowdahalli
G
Krishnegowda
Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
Andy
A
Awwad
Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
Alden
A
Dewey
Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
Xin
X
Liu
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.
Shantu
S
Amin
West China School of Pharmacy, Sichuan University, Chengdu, 610041, P. R. China.
Chunwei
C
Cheng
West China School of Pharmacy, Sichuan University, Chengdu, 610041, P. R. China.
Yong
Y
Qin
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612.
Ernst
E
Schonbrunn
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida 33612, and.
Gary
G
Daughdrill
Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
Thomas P
TP
Loughran
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612.
Said
S
Sebti
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: huw11@psu.edu.
Hong-Gang
HG
Wang
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles; D013449:Sulfonamides / Q000494:pharmacology*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C501332:ABT-737; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D013449:Sulfonamides; D051020:bcl-X Protein; C528298:marinopyrrole A; D046988:Proteasome Endopeptidase Complex