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.
Highlights
Taxanes are a family of natural products with a broad spectrum of anticancer activity
We performed a structure-based comparison using the PocketFeature algorithm to assess the similarity between the taxane pocket of beta-tubulin and the co-crystal structures retrieved from protein data bank (PDB) (Fig. 1a)[15]
For a given residue in the binding site, the geometric center of the residues was determined based on the location of the heavy atom and a 6 Å microenvironment consisting of 6-concentric radial shells of 480 physical and biochemical descriptors was evaluated around each residue locus[16,17]
Summary
Taxanes are a family of natural products with a broad spectrum of anticancer activity. Evaluation of nine selective estrogen receptor modulators (SERMs) via in vivo and in vitro assays confirmed taxane site interaction, microtubule stabilization, and cell proliferation inhibition.
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