# Targeting PFKFB3 kinase for activation of cell competition and elimination of dysfunctional beta-cells in type-2 diabetes

> **NIH NIH R41** · METANOIA BIO LLC · 2024 · $295,257

## Abstract

ABSTRACT
Type-2 diabetes (T2D) is the second most prevalent age-related disease, affecting a staggering 463 million
people worldwide. Its onset and progression are attributed to a progressive decline in β-cell function, where the
stressed β-cells resemble damaged (“loser”) cells that failed to undergo clearance by cell fitness competition
(CFC). In essence, CFC is a homeostatic process that embodies the constant monitoring for, and replacing of,
aged, injured, or dysfunctional cells in adult tissue with healthy fully functional (“winner”) cells. These β-cells
demonstrate a wide range of abnormalities, with the resultant metabolic stress correlating with an early loss of
β-cell glucose responsiveness prior to T2D onset. To date, different pharmacological approaches have focused
on increasing the insulin secretion of these dysfunctional -cells. We instead propose a model whereby β-cell
function is restored through the re-establishment of CFC.
Recent breakthrough studies from the Metanoia-UCLA collaboration demonstrated that hypoxia inducible factor-
1-alpha (HIF1) and its target 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) form a
signaling axis, which, when activated in the context of diabetes, remodels cellular metabolism to favor the survival
and block the removal of dysfunctional β-cells at the expense of β-cell function—mimicking the β-cell phenotype
in prediabetes. Using a novel “CFC” mouse model of diabetes, they were able to demonstrate that depletion of
PFKFB3 resulted in regeneration of functional β-cells.
Here, Metanoia will develop new composition entities (NCE) for PFKFB3 inhibition (Aim 2) and establish in vivo
proof-of-concept that pharmacologic targeting of PFKFB3 is able to restore CFC (Aim 1), thus triggering
functional -cell regeneration. This will include: (Aim 1.1) demonstrating that PFKFB3 targeting (depletion)
restores β-cell function, glucose tolerance, and insulin sensitivity, (Aim 1.2) determining the comparative efficacy
of PFKFB3 inhibitors to stably control glycemia alone and together with metformin vs. metformin alone, (Aim
1.3) establishing the durability of PFKFB3 inhibitor treatment; and by (Aim 2.1) designing new composition
entities (NCE) for PFKFB3 inhibition, and (Aim 2.2) performing simulation of molecular dynamics on select NCE
candidates.
In addition to the potential to significantly advance the current understanding of the underlying mechanism of
action of T2D, if successful, this study will lead to novel, patentable, first-in-class PFKFB3 inhibitor therapeutic
candidates that target the underlying mechanism of T2D. This treatment has potential to not only alter disease
trajectory in the short term, but also to be curative in the long term via islet enrichment with functional β-cells.

## Key facts

- **NIH application ID:** 10922398
- **Project number:** 1R41DK139901-01
- **Recipient organization:** METANOIA BIO LLC
- **Principal Investigator:** Oppel Greeff
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $295,257
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922398

## Citation

> US National Institutes of Health, RePORTER application 10922398, Targeting PFKFB3 kinase for activation of cell competition and elimination of dysfunctional beta-cells in type-2 diabetes (1R41DK139901-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10922398. Licensed CC0.

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