Pocket similarity identifies selective estrogen receptor modulators as microtubule modulators at the taxane site

Yu-Chen Lo, Olga Cormier, Tianyun Liu, Kendall W. Nettles, John A. Katzenellenbogen, Tim Stearns and Russ B. Altman ()
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Yu-Chen Lo: Stanford University
Olga Cormier: Stanford University
Tianyun Liu: Stanford University
Kendall W. Nettles: Scripps Research Institute
John A. Katzenellenbogen: University of Illinois-Urbana Champaign
Tim Stearns: Stanford University
Russ B. Altman: Stanford University

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08965-w

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