Microtubins: a novel class of small synthetic microtubule targeting drugs that inhibit cancer cell proliferation
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Silvia Senese1,*, Yu-Chen Lo1,2,*, Ankur A. Gholkar1, Chien-Ming Li3, Yong Huang3, Jack Mottahedeh4,5, Harley I. Kornblum4,5,6,7, Robert Damoiseaux4,8 and Jorge Z. Torres1,7,9
1Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA
2Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
3Drug Studies Unit, Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, CA 94143, USA
4Department of Molecular and Medical Pharmacology, Los Angeles, CA 90095, USA
5Department of Psychiatry, University of California, Los Angeles, CA 90095, USA
6The Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA
7Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA
8California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
9Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA
*These authors contributed equally to the work and are co-first authors
Jorge Z. Torres, email: [email protected]
Keywords: cell division, microtubules, cell cycle, tubulin-targeting agents, cancer cell proliferation
Received: June 01, 2017 Accepted: September 16, 2017 Published: October 19, 2017
Microtubule targeting drugs like taxanes, vinca alkaloids, and epothilones are widely-used and effective chemotherapeutic agents that target the dynamic instability of microtubules and inhibit spindle functioning. However, these drugs have limitations associated with their production, solubility, efficacy and unwanted toxicities, thus driving the need to identify novel antimitotic drugs that can be used as anticancer agents. We have discovered and characterized the Microtubins (Microtubule inhibitors), a novel class of small synthetic compounds, which target tubulin to inhibit microtubule polymerization, arrest cancer cells predominantly in mitosis, activate the spindle assembly checkpoint and trigger an apoptotic cell death. Importantly, the Microtubins do not compete for the known vinca or colchicine binding sites. Additionally, through chemical synthesis and structure-activity relationship studies, we have determined that specific modifications to the Microtubin phenyl ring can activate or inhibit its bioactivity. Combined, these data define the Microtubins as a novel class of compounds that inhibit cancer cell proliferation by perturbing microtubule polymerization and they could be used to develop novel cancer therapeutics.
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