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Pyoluteorin derivatives induce Mcl-1 degradation and apoptosis in hematological cancer cells.

Abstract
Mcl-1, a pro-survival member of the Bcl-2 protein family, is an attractive target for cancer therapy. We have recently identified the natural product marinopyrrole A (maritoclax) as a novel small molecule Mcl-1 inhibitor. Here, we describe the structure-activity relationship study of pyoluteorin derivatives based on maritoclax. To date, we synthesized over 30 derivatives of maritoclax and evaluated their inhibitory actions and cytotoxicity toward Mcl-1-dependent cell lines. As a result, several functional groups were identified in the pyoluteorin motif that significantly potentiate biological activity. A number of such derivatives, KS04 and KS18, interacted with Mcl-1 in a conserved fashion according to NMR spectroscopy and molecular modeling. KS04 and KS18 induced apoptosis selectively in Mcl-1-dependent but not Bcl-2-dependent K562 cells through selective Mcl-1 down-regulation, and synergistically enhanced apoptosis in combination with ABT-737. Moreover, the intraperitoneal administration of KS18 (10 mg/kg/d) and ABT-737 (20 mg/kg/d) significantly suppressed the growth of ABT-737-resistant HL-60 xenografts in nude mice without apparent toxicity. Overall, we identified the pharmacophore of pyoluteorin derivatives that act as potent and promising Mcl-1 antagonists against Mcl-1-dependent hematological cancers.
AuthorsKenichiro Doi, Krishne Gowda, Qiang Liu, Jyh-Ming Lin, Shen-Shu Sung, Christopher Dower, David Claxton, Thomas P Loughran Jr, Shantu Amin, Hong-Gang Wang
JournalCancer biology & therapy (Cancer Biol Ther) Vol. 15 Issue 12 Pg. 1688-99 ( 2014) ISSN: 1555-8576 [Electronic] United States
PMID25535900 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Phenols
  • Pyrroles
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • marinopyrrole A
  • pyoluteorin
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Female
  • Hematologic Neoplasms (metabolism, pathology)
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, chemistry, metabolism)
  • Phenols (chemistry, metabolism, pharmacology)
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Proteolysis (drug effects)
  • Pyrroles (chemistry, metabolism, pharmacology)
  • Stromal Cells (drug effects, metabolism)
  • Time Factors
  • Tumor Burden (drug effects)
  • Xenograft Model Antitumor Assays
  • bcl-2 Homologous Antagonist-Killer Protein (metabolism)
  • bcl-2-Associated X Protein (metabolism)

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