# New anti-glioblastoma metabolic compounds with high potential for Blood Brain Barrier penetration

> **NIH NIH R41** · WAYPATH PHARMA LLC · 2022 · $225,000

## Abstract

Glioblastomas are very aggressive tumors of the central nervous system (CNS) with a median patient survival
of about 16 months. Therapeutic options for glioblastoma patients are very limited mostly because the majority
of potential anti-cancer drugs do not cross the blood brain barrier (BBB). In addition, recently tested
immunotherapies including immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapies failed to
produce a positive outcome in glioblastoma patients. Surprisingly, metabolic approaches including calorie
restriction and ketogenic diet demonstrate promising results as supplemental therapies for glioblastoma patients.
In this regard, multiple studies, including our research, show that a common lipid-lowering prodrug, fenofibrate
(FF), triggers a severe energetic crisis in glioblastoma cells by compromising the function of Complex 1 of the
electron transport chain (ETC), leading to the extensive glioblastoma cell death. However, FF does not cross the
BBB and is quickly processed by blood and tissue esterases to fenofibric acid, which is a potent PPARµ agonist,
no longer effective in killing glioblastoma cells. Therefore, we have made several chemical modifications in the
FF molecular skeleton to construct a new family of drugs with high anti-glioblastoma potential. In this proposal,
we attempt to test the overall hypothesis that specific chemical modification/s in the common molecular skeleton
of FF, benzyl-phenoxy-acetamide (BPA), will result in a new anti-glioblastoma metabolic drug/s that are stable,
capable of crossing the BBB, and effective in triggering glioblastoma cell death at low µM concentrations. Our
preliminary results indicate that two new drug candidates designated here, as MT1 and MT3, have very promising
characteristics for BBB penetration. To evaluate these compounds, we have developed a comprehensive
experimental approach consisting of: a) computational modeling of the BPA molecular structure by applying the
Central Nervous System – Multiparameter Optimization (CNS-MPO) algorithm; b) development of the most
effective strategy for synthesis and testing of chemical integrity and purity of the new compound; c) in vitro testing
for glioblastoma cytotoxicity and the mechanism of action; and d) Pharmacokinetic analyses of the compound
bioavailability, maximal tolerated dose (MTD) and anti-glioblastoma efficacy in highly relevant animal models.

## Key facts

- **NIH application ID:** 10543931
- **Project number:** 1R41CA275433-01
- **Recipient organization:** WAYPATH PHARMA LLC
- **Principal Investigator:** Krzysztof Reiss
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $225,000
- **Award type:** 1
- **Project period:** 2022-09-02 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10543931

## Citation

> US National Institutes of Health, RePORTER application 10543931, New anti-glioblastoma metabolic compounds with high potential for Blood Brain Barrier penetration (1R41CA275433-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10543931. Licensed CC0.

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