# Optimization of a novel class of microtubule stabilizers

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $344,020

## Abstract

Microtubule stabilizing agents (MSAs) are some of the most widely used and effective therapies available
for the treatment of solid tumors. However, their utility is compromised by innate and acquired drug
resistance. The taccalonolides (taccas) are a mechanistically unique class of MSAs that circumvent
multiple clinically relevant forms of drug resistance. Multiple potent taccas identified by our laboratories
have effective antitumor activity in drug sensitive and resistant in vivo models but suffer from a narrow
therapeutic window. This project will develop an in depth understanding of the pharmacokinetics and
pharmacodynamics of this class of MSAs that will yield taccas with an optimal in vivo profile for future
clinical development. The recent generation of a crystal structure of a tacca bound to tubulin
heterodimers has provided unprecedented insight into the tacca pharmacophore, which will be used to
experimentally define the critical residues on tubulin and moieties on the taccas that mediate their novel
mechanism of microtubule stabilizing activity. We have also identified sites on the tacca skeleton that can
be modified semi-synthetically to improve compound stability and optimize their pharmacokinetic profile
and antitumor actions. Functional fluorescent and biotin-tagged taccas have been generated that will
allow, for the first time, direct detection of the taccas in vitro and in vivo that will be instrumental in
understanding the uptake, distribution, and target binding of this unique MSA. In addition to generating
taccas with a more favorable pharmacokinetic profile and evaluating their efficacy in molecularly defined
patient derived tumor xenograft and syngeneic models, we will also determine biomarkers associated
with response to this novel class of MSAs. Expression analysis in a panel of molecularly defined triple
negative breast cancer cell lines identified signaling pathways that correlate with the cytotoxic efficacy of
the taccas. We will further evaluate whether intrinsic alterations in these signaling pathways are
biomarkers of drug response and, reciprocally, follow up on data indicating that the taccas can also alter
the functional consequences of these signaling pathways. These studies are significant in that they will
lead, in the future, to the generation of a clinical lead candidate for the treatment of drug resistant solid
tumors and a greater understanding of their mechanism of action and predictors of response.

## Key facts

- **NIH application ID:** 10122918
- **Project number:** 5R01CA219948-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** April L Risinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,020
- **Award type:** 5
- **Project period:** 2018-04-17 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122918

## Citation

> US National Institutes of Health, RePORTER application 10122918, Optimization of a novel class of microtubule stabilizers (5R01CA219948-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10122918. Licensed CC0.

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