# Evaluation of Novel Dually Targeted Kinase Inhibitors for Therapy of Adult and Pediatric High-Grade Glioma

> **NIH NIH R33** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $335,679

## Abstract

PROJECT SUMMARY
High grade gliomas in both adults and children confer very poor prognosis, with median survival rates under
two years post diagnosis. Amplification of epidermal growth factor receptor (EGFR) and platelet derived growth
factor receptor (PDGFR), as well as mutations in the PI3K/AKT/mTOR pathway are frequent and can be
targeted by kinase inhibitor based strategies. EGFR inhibition has been tested clinically, but responses have
been limited. Inadequate target engagement, perhaps due to poor blood brain barrier penetrance, as well as
downregulation or circumvention of the target in recurrent tumors, are amongst mechanisms cited for lack of
efficacy of EGFR-targeted agents. Combination strategies using PI3K and MAPK inhibitors are promising, and
can overcome acquired resistance to single agents in GBM. Advantages of using a single molecule to target
multiple kinases include reduced risks of drug interactions, a single pharmacokinetic profile for optimization of
dosing, and increased potential for overcoming drug resistance. Therefore, the development of therapeutics
that target more than one kinase, identification of biomarkers of response and careful evaluation of BBB
permeance are imperative to improving patient outcomes. Employing a computational modeling approach, we
exploited the known binding modes of structurally related ATP binding site inhibitors of EGFR and PI3K to
design small molecules that simultaneously inhibit both kinases in a selective manner. We hypothesize
that this polypharmacology approach will provide better efficacy in vitro and in vivo compared to multi-drug
combination strategies. Preliminary data generated in human glioblastoma and patient derived pediatric
diffuse intrinsic pontine glioma (DIPG) lines shows potent cytotoxic effects of these dually targeted agents
relative to targeting of EGFR alone or PI3K alone. Furthermore, we have identified unique metabolic features
of the inhibitors, indicating suppression of both glycolytic pathways and oxidative phosphorylation, which is not
seen with clinically relevant EGFR or PI3K inhibitors. We posit that this will lead to the development of
metabolomics based biomarkers. In Year 1, in the R61 phase of this application, we will further optimize the
pharmaceutical features of this chemical series of compounds to increase the likelihood of blood-brain barrier
(BBB) penetrance. We have generated key preliminary data showing that MTX-241 possess critical attributes
for BBB permeability. Therefore we will use in vivo models to test MTX-241, while simultaneously synthesizing
and evaluating 15-20 structural analogs of MTX-241. The R33 phase of the proposal will be carried out in
Years 2 and 3, whereupon we will focus on in vivo evaluation of the two most promising candidates identified
using orthotopic models to address anti-tumor efficacy, blood brain barrier permeance, and biomarkers of drug
action. These studies have been designed to support our hypothesis that a single...

## Key facts

- **NIH application ID:** 10164961
- **Project number:** 4R33NS111058-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Joya Chandra
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,679
- **Award type:** 4N
- **Project period:** 2019-05-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164961

## Citation

> US National Institutes of Health, RePORTER application 10164961, Evaluation of Novel Dually Targeted Kinase Inhibitors for Therapy of Adult and Pediatric High-Grade Glioma (4R33NS111058-02). Retrieved via AI Analytics 2026-06-04 from https://api.ai-analytics.org/grant/nih/10164961. Licensed CC0.

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