Microtubule stabilizers are valuable drugs used in the treatment of cancer. The focus of this project is a new class of plant-derived microtubule stabilizers, the taccalonolides. The taccalonolides have distinct effects on interphase microtubule bundling, mitotic spindle morphology and mitotic signaling pathways. Potent new taccalonolides have been identified for the first time and they robustly polymerize purified tubuli indicating a direct interaction with tubulin/microtubules. The tubulin polymerization experiments also indicate that the taccalonolides interact with tubulin in a manner different from other microtubule stabilizers. Our preliminary data suggest that the taccalonolides bind within a unique site on tubulin. All of the taccalonolides overcome clinically relevant mechanisms of drug resistance and the taccalonolides A and E have in vivo antitumor activity against a paclitaxel and doxorubicin-resistant murine model of breast cancer. Comprehensive studies are proposed to identify the tubulin binding site of the taccalonolides, the functional significance of this bining and how this interrupts mitotic and interphase signaling downstream. These studies are expected to identify a new tubulin binding site or pharmacophore for stabilizing microtubules.
The first aim will identify the binding site of the taccalonolides on tubulin/microtubules utilizin complementary structural biology approaches.
The second aim describes the functional significance of the taccalonolide interaction with tubulin/microtubules biochemically and in cells.
This aim will identify the effects of the potent taccalonolides on purified tubulin and on cellular microtubule dynamics. We anticipate that interruption of microtubule dynamics leads to mitotic signaling and interphase microtubule trafficking defects and ultimately cell death. The last aim will examine the structure-activity relationships of the taccalonolides to identify the specific chemical moieties necessary for optimal biological activities. Information gained from these studies will elucidate the chemical and biological properties of this new class of microtubule stabilizers. This is expected to lead to the identification of a new microtubule stabilizer binding site on tubulin that will provide new opportunities for rational drug development with the possibility of a unique spectrum of activity.

Public Health Relevance

Microtubule stabilizing agents, including most notably the taxanes, represent some of the most valuable agents used for the treatment of cancer. We have identified potent microtubule stabilizers, the taccalonolides that bind to tubulin, have distinct effects and the potential to overcome the limitations of the taxanes. We will identify the tubulin binding site of the taccalonolides, how they stabilize microtubules, interrupt interphase and mitotic signaling pathways as well as the chemical moieties critical for optimal biological effects

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121138-08
Application #
8530175
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Fu, Yali
Project Start
2006-04-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$242,208
Indirect Cost
$80,196
Name
University of Texas Health Science Center San Antonio
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Li, Jing; Risinger, April L; Mooberry, Susan L (2014) Taccalonolide microtubule stabilizers. Bioorg Med Chem 22:5091-6
Peng, Jiangnan; Risinger, April L; Li, Jing et al. (2014) Synthetic reactions with rare taccalonolides reveal the value of C-22,23 epoxidation for microtubule stabilizing potency. J Med Chem 57:6141-9
Rohena, Cristina C; Mooberry, Susan L (2014) Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities. Nat Prod Rep 31:335-55
Risinger, April L; Riffle, Stephen M; Lopus, Manu et al. (2014) The taccalonolides and paclitaxel cause distinct effects on microtubule dynamics and aster formation. Mol Cancer 13:41
Li, Jing; Peng, Jiangnan; Risinger, April L et al. (2013) Hydrolysis reactions of the taccalonolides reveal structure-activity relationships. J Nat Prod 76:1369-75
Risinger, April L; Peng, Jiangnan; Rohena, Cristina C et al. (2013) The bat flower: a source of microtubule-destabilizing and -stabilizing compounds with synergistic antiproliferative actions. J Nat Prod 76:1923-9
Risinger, A L; Li, J; Bennett, M J et al. (2013) Taccalonolide binding to tubulin imparts microtubule stability and potent in vivo activity. Cancer Res 73:6780-92
Risinger, April L; Mooberry, Susan L (2011) Cellular studies reveal mechanistic differences between taccalonolide A and paclitaxel. Cell Cycle 10:2162-71
Risinger, April L; Natarajan, Mohan; Thomas Jr, Charles R et al. (2011) The taccalonolides, novel microtubule stabilizers, and ýý-radiation have additive effects on cellular viability. Cancer Lett 307:104-11
Li, Jing; Risinger, April L; Peng, Jiangnan et al. (2011) Potent taccalonolides, AF and AJ, inform significant structure-activity relationships and tubulin as the binding site of these microtubule stabilizers. J Am Chem Soc 133:19064-7

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