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Pyoluteorin derivatives induce Mcl-1 degradation and apoptosis in hematological cancer cells
- Source :
- Cancer Biology & Therapy. 15:1688-1699
- Publication Year :
- 2014
- Publisher :
- Informa UK Limited, 2014.
-
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.
- Subjects :
- Models, Molecular
Cancer Research
Time Factors
Cell Survival
Molecular Conformation
Antineoplastic Agents
Apoptosis
Pharmacology
Bcl-2-associated X protein
Phenols
Cell Line, Tumor
hemic and lymphatic diseases
Animals
Humans
Protein Interaction Domains and Motifs
Pyrroles
Cytotoxicity
bcl-2-Associated X Protein
biology
Bcl-2 family
Drug Synergism
Biological activity
Xenograft Model Antitumor Assays
Tumor Burden
Cell biology
Disease Models, Animal
bcl-2 Homologous Antagonist-Killer Protein
Oncology
Drug Resistance, Neoplasm
Hematologic Neoplasms
Proteolysis
Cancer cell
biology.protein
Myeloid Cell Leukemia Sequence 1 Protein
Molecular Medicine
Female
Stromal Cells
Pharmacophore
Bcl-2 Homologous Antagonist-Killer Protein
Research Paper
Protein Binding
Subjects
Details
- ISSN :
- 15558576 and 15384047
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Cancer Biology & Therapy
- Accession number :
- edsair.doi.dedup.....a85b89f3a997d415897ba86b030a2615