TY - JOUR
T1 - Pocket similarity identifies selective estrogen receptor modulators as microtubule modulators at the taxane site
AU - Lo, Yu Chen
AU - Cormier, Olga
AU - Liu, Tianyun
AU - Nettles, Kendall W.
AU - Katzenellenbogen, John A.
AU - Stearns, Tim
AU - Altman, Russ B.
N1 - We thank all members of the Helix group and Stearns lab at Stanford University for their helpful feedback and suggestions. We also thank the lab of Scott J. Dixon for live imaging instrument time. The project was supported by a Stanford School of Medicine Dean’s Postdoctoral Fellowship, Stanford Graduate Fellowship, and the following funding sources: NIH GM102365, LM05652, HL117798, R01CA220284, and R01GM121424. The project described was supported, in part, by ARRA Award Number 1S10RR026780-01 from the National Center for Research Resources (NCRR). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or the National Institutes of Health.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-08965-w
DO - 10.1038/s41467-019-08965-w
M3 - Article
C2 - 30833575
AN - SCOPUS:85062400142
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1033
ER -