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

Kenichiro Doi, Krishne Gowda, Qiang Liu, Jyh ming Lin, Shen-shu Sung, Christopher Dower, David Claxton, Thomas P. Loughran, Shantu Amin, Hong-Gang Wang

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Mcl-1, a pro-survival member of the Bcl-2 protein family, is an attractive target for cancer therapy. We have recently identifi ed 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.

Original languageEnglish (US)
Pages (from-to)1688-1699
Number of pages12
JournalCancer Biology and Therapy
Volume15
Issue number12
DOIs
StatePublished - Dec 1 2014

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Apoptosis
Neoplasms
K562 Cells
Structure-Activity Relationship
Biological Products
Heterografts
Nude Mice
Magnetic Resonance Spectroscopy
Down-Regulation
Cell Line
marinopyrrole A
pyoluteorin
Growth
ABT-737
Proteins
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

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title = "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 identifi ed 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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Pyoluteorin derivatives induce Mcl-1 degradation and apoptosis in hematological cancer cells. / Doi, Kenichiro; Gowda, Krishne; Liu, Qiang; Lin, Jyh ming; Sung, Shen-shu; Dower, Christopher; Claxton, David; Loughran, Thomas P.; Amin, Shantu; Wang, Hong-Gang.

In: Cancer Biology and Therapy, Vol. 15, No. 12, 01.12.2014, p. 1688-1699.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pyoluteorin derivatives induce Mcl-1 degradation and apoptosis in hematological cancer cells

AU - Doi, Kenichiro

AU - Gowda, Krishne

AU - Liu, Qiang

AU - Lin, Jyh ming

AU - Sung, Shen-shu

AU - Dower, Christopher

AU - Claxton, David

AU - Loughran, Thomas P.

AU - Amin, Shantu

AU - Wang, Hong-Gang

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Y1 - 2014/12/1

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