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An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

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Abstract

Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.

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Abbreviations

2-ME:

2-methoxyestradiol

ABC:

ATP binding cassette

BS:

binding site

CA-4:

combretastatin A-4

CBSI:

colchicine binding site inhibitors

cGMP:

cyclic guanosine monophosphate

CNS:

central nervous system

CoMFA:

comparative molecular field analyses

CoMSIA:

comparative molecular similarity indices analyses

DAMA-colchicine:

N-deacetyl-N-(2-mercaptoacetyl) colchicine

FDA:

Food and Drug Administration

FGF:

fibroblast growth factor

HIF:

hypoxia-inducible factor

HUVEC:

human umbilical vein endothelial cell

LIE:

linear interaction energy

MDR:

multidrug resistance

MRP:

multidrug resistance-associated protein

MTA:

microtubule targeting agent

NCI:

National Cancer Institute

PDE:

phosphodiesterase

Pgp:

P-glycoprotein

PK:

pharmacokinetic

QSAR:

quantitative structure-activity relationships

SAR:

structure-activity relationship

SGB:

surface-generalized Born

TMP:

trimethoxyphenyl

TNF-α:

tumor necrosis factor-α

VDA:

vascular-disrupting agent

VEGFR:

vascular endothelial growth factor receptor

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Acknowledgments & Disclosures

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA148706. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional supports were provided by the Van Vleet Endowed Professorship.

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Lu, Y., Chen, J., Xiao, M. et al. An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site. Pharm Res 29, 2943–2971 (2012). https://doi.org/10.1007/s11095-012-0828-z

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