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.
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Authors | Kenichiro Doi, Krishne Gowda, Qiang Liu, Jyh-Ming Lin, Shen-Shu Sung, Christopher Dower, David Claxton, Thomas P Loughran Jr, Shantu Amin, Hong-Gang Wang |
Journal | Cancer biology & therapy
(Cancer Biol Ther)
Vol. 15
Issue 12
Pg. 1688-99
( 2014)
ISSN: 1555-8576 [Electronic] United States |
PMID | 25535900
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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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
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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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