ArticleThe Journal of biological chemistry2012
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.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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Who cites it
85 citing papers in PubMed, 156 citations in OpenAlex.
- Targeted Degradation of MCL-1 by PROTAC Mcl-1 Degrader-1 Exhibits Antiproliferative and Antimigratory Effects and Triggers Mitochondria-Mediated Apoptosis in Colorectal Cancer.Current issues in molecular biology · 2026Article
- Broad-Spectrum Anti-Infective Activity of Natural Compounds Pyrrolomycins, Marinopyrroles, and Their Analogs.Pathogens (Basel, Switzerland) · 2026Review
- DrugBank mining with machine learning reveals novel candidates for BCL-2 inhibition.Scientific reports · 2026Article
- Saga of MCL1 inhibitors in multiple myeloma.Biochemical pharmacology · 2026Review
- Maritoclax Overcomes FBW7 Deficiency-Driven Irinotecan Resistance in Colorectal Cancer by Targeting MCL1.Cancer medicine · 2025Article
- Cancer Cell Cytotoxicity of Marinopyrroles, Pyrrolomycins, and Their Derivatives.Marine drugs · 2025Review
- Expanded Gram-Negative Activity of Marinopyrrole A.Pathogens (Basel, Switzerland) · 2025Article
- An Optimized Marinopyrrole A Derivative Targets 6-Phosphoglucosamine Synthetase to Inhibit Methicillin-ResistantACS central science · 2024Article
- Antibacterial Marinopyrroles and Pseudilins Act as Protonophores.ACS chemical biology · 2024Article
- Marinopyrrole derivative MP1 as a novel anti-cancer agent in group 3 MYC-amplified Medulloblastoma.Journal of experimental & clinical cancer research : CR · 2024Article
- In silico design and cell-based evaluation of two dual anti breast cancer compounds targeting Bcl-2 and GPER.Scientific reports · 2023Article
- Past, Present, and a Glance into the Future of Multiple Myeloma Treatment.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Mechanisms of MCL-1 Protein Stability Induced by MCL-1 Antagonists in B-Cell Malignancies.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Natural Products from Actinobacteria as a Potential Source of New Therapies Against Colorectal Cancer: A Review.Frontiers in pharmacology · 2022Review
- Therapeutic effects of an innovative BS-HH-002 drug on pancreatic cancer cells via induction of complete MCL-1 degradation.Translational oncology · 2022Article
- Non-coding RNA-related antitumor mechanisms of marine-derived agents.Frontiers in pharmacology · 2022Review
- Myeloid cell leukemia-1: a formidable barrier to anticancer therapeutics and the quest of targeting it.Exploration of targeted anti-tumor therapy · 2022Review
- Targeting MCL-1 in cancer: current status and perspectives.Journal of hematology & oncology · 2021Review
- Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells.Scientific reports · 2021Article
- Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity.Cell reports. Medicine · 2021Article
25 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 5 institutions in 2 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.