# Brain Penetrant Microtubule-Stabilizers to Treat CNS-invasive Parasitic Diseases

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $252,094

## Abstract

PROJECT SUMMARY
Microtubules (MTs) constitute an essential component of the cytoskeleton in all eukaryotic cells and are involved
in a number of important structural and regulatory functions, including the maintenance of cell shape, intracellular
transport machinery, motility, as well as cell growth and division. MT-targeting drugs, which include MT-
stabilizing and -destabilizing compounds, form a cornerstone of cancer chemotherapy; however, several studies
suggest that such compounds may be also useful to treat other human diseases, including parasitic infections.
From their ongoing studies to combat neurodegenerative diseases, the groups of Dr. Ballatore (UC San Diego)
and Dr. Brunden (University of Pennsylvania) have synthesized and characterized a target-based library of >250
small molecules that are known to engage MTs and exhibit generally favorable drug-like properties, including
brain penetration and oral bioavailability. This target-based library of non-commercially available compounds
offers, therefore, an unique ‘re-tooling’ opportunity to develop new therapeutic leads for neuroparasitic diseases,
such as Stage 2 Human African trypanosomiasis (HAT; Sleeping Sickness) and Primary Amebic
Meningoencephalitis (PAM), which are caused by Trypanosoma brucei and Naegleria fowleri, respectively.
Accordingly, our preliminary studies confirm that members of the triazolopyrimidine (TPD) and phenylpyrimidine
(PPD) classes of MT-active compounds within our compound library kill N. fowleri and/or T. brucei with potencies
equivalent to or exceeding those of the current drug standards. Representative compounds from this anti-
parasitic subset have also undergone full pharmacokinetic (PK) analyses and in vitro safety pharmacology
assessments suggesting the compounds are appropriate for in vivo anti-parasite efficacy studies. Thus, the goal
of the R21 phase of this proposal is to: (a) complete the in vitro screening of available TPDs and PPDs; (b)
determine the brain penetration of the most promising compounds; (c) conduct full PK and tolerability studies on
selected molecules; and (d) conduct in vivo proof-of-concept experiments in animal models of HAT and PAM.
Completion of the R21 studies will lead to the R33 phase, which will be focused on structure activity relationships,
lead optimization, and mode of action studies.

## Key facts

- **NIH application ID:** 9852970
- **Project number:** 5R21AI141210-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Carlo Ballatore
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $252,094
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852970

## Citation

> US National Institutes of Health, RePORTER application 9852970, Brain Penetrant Microtubule-Stabilizers to Treat CNS-invasive Parasitic Diseases (5R21AI141210-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852970. Licensed CC0.

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