Position of lipidation influences anticancer activity of Smac analogs.

Antineoplastic Agents / pharmacology Apoptosis Regulatory Proteins / pharmacology Cell Line, Tumor Humans Mitochondrial Proteins / pharmacology Neoplasms / drug therapy
Anticancer agents Apoptosis Inhibitor of menin–MLL1 protein interactions Lipid-conjugated peptides S-alkylation of peptides Smac mimetics

Journal

Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377

Informations de publication

Date de publication:
01 07 2019
Historique:
received: 11 03 2019
revised: 25 04 2019
accepted: 25 04 2019
pubmed: 3 5 2019
medline: 10 9 2020
entrez: 4 5 2019
Statut: ppublish

Résumé

A small group of lipid-conjugated Smac mimetics was synthesized to probe the influence of the position of lipidation on overall anti-cancer activity. Specifically, new compounds were modified with lipid(s) in position 3 and C-terminus. Previously described position 2 lipidated analog M11 was also synthesized. The resulting mini library of Smacs lipidated in positions 2, 3 and C-terminus was screened extensively in vitro against a total number of 50 diverse cancer cell lines revealing that both the position of lipidation as well as the type of lipid, influence their anti-cancer activity and cancer type specificity. Moreover, when used in combination therapy with inhibitor of menin-MLL1 protein interactions, position 2 modified analog SM2 showed strong synergistic anti-cancer properties. The most promising lipid-conjugated analogs SM2 and SM6, showed favorable pharmacokinetics and in vivo activity while administered subcutaneously in the preclinical mouse model. Collectively, our findings suggest that lipid modification of Smacs may be a viable approach in the development of anti-cancer therapeutic leads.

Identifiants

DOI: 10.1016/j.bmcl.2019.04.041 PMID: 31047753 PMC: PMC6625762
pubmed: 31047753
pii: S0960-894X(19)30274-4
doi: 10.1016/j.bmcl.2019.04.041
pmc: PMC6625762
mid: NIHMS1528176
pii:
doi:

Substances chimiques

Antineoplastic Agents 0
Apoptosis Regulatory Proteins 0
DIABLO protein, human 0
Mitochondrial Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1628-1635

Subventions

Organisme : NIAID NIH HHS
ID : U19 AI067769
Pays : United States

Informations de copyright

Copyright © 2019 Elsevier Ltd. All rights reserved.

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Auteurs

Ewa D Micewicz (ED)

Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.

Christine Nguyen (C)

Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.

Alina Micewicz (A)

David Geffen School of Medicine at UCLA, Volunteering Program, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.

Alan J Waring (AJ)

Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA.

William H McBride (WH)

Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.

Piotr Ruchala (P)

Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA; The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Los Angeles, CA 90024, USA. Electronic address: pruchala@mednet.ucla.edu.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Position of lipidation influences anticancer...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines régulatrices de l'apoptose › Position of lipidation influences anticancer...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Position of lipidation influences anticancer...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Position of lipidation influences anticancer...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines mitochondriales › Position of lipidation influences anticancer...
questionsmedicales.fr › Tumeurs › Position of lipidation influences anticancer...