# m6A-RNA demethylase ALKBH5 inhibitors for the treatment of glioblastoma

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $433,813

## Abstract

Epitranscriptomics is an emerging field that seeks to identify and understand chemical
modifications in RNA; the enzymes that deposit, remove, and interpret the modifications
(writers, erasers, and readers, respectively); and their effects on gene expression via regulation
of RNA metabolism, function, and localization. Glioblastoma multiforme (GBM) is the deadliest
brain tumor identified in both adults and children, with an average life expectancy of 15 months.
GBM is characterized by high rates of both tumor infiltration and recurrence and is often
resistant to treatment with radiation and chemotherapy. These characteristics have been
attributed to the presence of undifferentiated glioblastoma tumor-initiating cells or glioblastoma
stem-like tumor initiating cells (GSCs). Recent studies have shown that cells depleted in N6-
methyladenosine (m6A) RNA modifications are resistant to differentiation, and it is suspected
that misregulation of the reversible m6A pathway may play a role in generating tumor-initiating
cells and promoting tumorigenesis. ALKBH5 expression is elevated in primary and established
GBM cells enriched with GSCs, and high expression is correlated with poor prognosis in GBM
patients. The objective of this proposal is to identify and develop novel inhibitors of the RNA
demethylase alkylation repair homolog protein 5 (ALKBH5) as potential chemotherapeutics for
glioblastoma multiforme. Our project has three aims. Aim 1: to optimize leads as potent and
selective inhibitors of ALKBH5 with rational drug design. Aim 2: to establish the enzymatic and
cellular mechanism of action of ALKBH5 inhibitors. Aim 3: to establish ALKBH5 inhibitors as
effective antiproliferative agents in GSCs. The expected outcome of this work is a chemically
diverse set of the first ALKBH5 inhibitors. This project will provide a clear positive impact by
providing important groundwork for developing ALKBH5-targeted treatments of GBM.

## Key facts

- **NIH application ID:** 10043670
- **Project number:** 1R21NS118250-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** TARIQ M RANA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $433,813
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10043670

## Citation

> US National Institutes of Health, RePORTER application 10043670, m6A-RNA demethylase ALKBH5 inhibitors for the treatment of glioblastoma (1R21NS118250-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10043670. Licensed CC0.

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