# Targeting proton-sensing GPR68 as a ferroptosis-based therapy for glioblastoma

> **NIH NIH R43** · PROTON BIO, INC. · 2024 · $399,214

## Abstract

Glioblastoma (GBM) is the most common primary brain cancer in adults. Over 10,000 people are estimated to
die yearly from GBM despite aggressive treatment, and there has been no substantial improvement in GBM
patient survival for more than four decades (5-year survival rate: mid-1970s 4% vs. 7% today), emphasizing the
need for new therapies. A hallmark of GBM is an acidic tumor microenvironment, which promotes tumor
progression. GPR68 is a proton-sensing G-protein-coupled receptor activated in response to an acidic
microenvironment and implicated in cancer-related processes. Proton Bio co-founders identified the first class
of specific GPR68 inhibitors, the ogremorphins, that potently kill a diverse panel of GBM cells through ferroptosis,
a novel form of iron-dependent regulated cell death, even those resistant to first-line therapy temozolomide,
providing the foundation for the hypothesis that targeting GPR68 represents a novel therapeutic approach
against GBM. While the parent ogremorphin had poor pharmacological properties that precluded in vivo
validation of this hypothesis, structure-activity relationship analysis yielded improved analogs. Three analogs
have been selected as lead candidates. The objectives of this Phase I project are to select a lead ogremorphin
and to perform critical proof-of-concept testing in orthotopic GBM patient-derived xenografts (PDXs). To achieve
these objectives, the following three specific aims will be pursued: 1) define the in vitro pharmacological
properties of the ogremorphin lead candidates, 2) determine the detailed PK/brain accumulation profiles of
ogremorphin lead candidates, and 3) demonstrate proof-of-concept that targeting GPR68 with the lead
ogremorphin is efficacious against GBM in vivo. In Aim 1, the three lead candidates will be compared side-by-
side for plasma protein binding, cytochrome P450 inhibition, microsomal stability, and hERG inhibition. In Aim 2,
the pharmacokinetics and brain penetration of the lead candidates will be determined following oral
administration in CD-1 mice. From the data generated in Aims 1 and 2, the lead ogremorphin will be selected. In
Aim 3, critical proof-of-concept efficacy studies will be performed using orthotopic temozolomide-sensitive and
temozolomide-resistant GBM PDX models. Treatment effects will be monitored by survival, MRI analysis of tumor
growth, histology and immunohistochemistry. Successful establishment of proof-of-concept will validate GPR68
as a therapeutic target in GBM and move the lead ogremorphin into development. The development of GRP68
inhibitors as therapeutics could potentially revolutionize GBM treatment and finally bring about a welcome shift
in the 5-year survival of GBM patients.

## Key facts

- **NIH application ID:** 10819403
- **Project number:** 1R43CA287513-01
- **Recipient organization:** PROTON BIO, INC.
- **Principal Investigator:** Charles Houston Williams
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $399,214
- **Award type:** 1
- **Project period:** 2024-08-07 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819403

## Citation

> US National Institutes of Health, RePORTER application 10819403, Targeting proton-sensing GPR68 as a ferroptosis-based therapy for glioblastoma (1R43CA287513-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10819403. Licensed CC0.

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