Pocket similarity identifies selective estrogen receptor modulators as microtubule modulators at the taxane site.
Antineoplastic Agents
/ chemistry
Binding Sites
Bridged-Ring Compounds
/ chemistry
Cell Death
/ drug effects
Cell Line, Tumor
/ drug effects
Cell Proliferation
/ drug effects
Humans
Ligands
Microtubule Proteins
/ drug effects
Models, Molecular
Paclitaxel
/ pharmacology
Selective Estrogen Receptor Modulators
/ chemistry
Taxoids
/ chemistry
Tubulin
/ chemistry
Tubulin Modulators
/ chemistry
Tumor Microenvironment
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 03 2019
04 03 2019
Historique:
received:
27
04
2018
accepted:
19
01
2019
entrez:
6
3
2019
pubmed:
6
3
2019
medline:
24
4
2019
Statut:
epublish
Résumé
Taxanes are a family of natural products with a broad spectrum of anticancer activity. This activity is mediated by interaction with the taxane site of beta-tubulin, leading to microtubule stabilization and cell death. Although widely used in the treatment of breast cancer and other malignancies, existing taxane-based therapies including paclitaxel and the second-generation docetaxel are currently limited by severe adverse effects and dose-limiting toxicity. To discover taxane site modulators, we employ a computational binding site similarity screen of > 14,000 drug-like pockets from PDB, revealing an unexpected similarity between the estrogen receptor and the beta-tubulin taxane binding pocket. Evaluation of nine selective estrogen receptor modulators (SERMs) via cellular and biochemical assays confirms taxane site interaction, microtubule stabilization, and cell proliferation inhibition. Our study demonstrates that SERMs can modulate microtubule assembly and raises the possibility of an estrogen receptor-independent mechanism for inhibiting cell proliferation.
Identifiants
pubmed: 30833575
doi: 10.1038/s41467-019-08965-w
pii: 10.1038/s41467-019-08965-w
pmc: PMC6399299
doi:
Substances chimiques
Antineoplastic Agents
0
Bridged-Ring Compounds
0
Ligands
0
Microtubule Proteins
0
Selective Estrogen Receptor Modulators
0
Taxoids
0
Tubulin
0
Tubulin Modulators
0
taxane
1605-68-1
Paclitaxel
P88XT4IS4D
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
1033Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM130286
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM102365
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220284
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM121424
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR026780
Pays : United States
Organisme : NHLBI NIH HHS
ID : U54 HL117798
Pays : United States
Organisme : NLM NIH HHS
ID : R01 LM005652
Pays : United States
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