Microtubins: a novel class of small synthetic microtubule targeting drugs that inhibit cancer cell proliferation

// Silvia Senese 1, * , Yu-Chen Lo 1, 2, * , Ankur A. Gholkar 1 , Chien-Ming Li 3 , Yong Huang 3 , Jack Mottahedeh 4, 5 , Harley I. Kornblum 4, 5, 6, 7 , Robert Damoiseaux 4, 8 and Jorge Z. Torres 1, 7, 9 1 Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA 2 Department of Bioengineering, University of California, Los Angeles, CA 90095, USA 3 Drug Studies Unit, Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, CA 94143, USA 4 Department of Molecular and Medical Pharmacology, Los Angeles, CA 90095, USA 5 Department of Psychiatry, University of California, Los Angeles, CA 90095, USA 6 The Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA 7 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA 8 California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA 9 Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA * These authors contributed equally to the work and are co-first authors Correspondence to: Jorge Z. Torres, email: torres@chem.ucla.edu Keywords: cell division, microtubules, cell cycle, tubulin-targeting agents, cancer cell proliferation Received: June 01, 2017      Accepted: September 16, 2017      Published: October 19, 2017 ABSTRACT 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.