# Development of AMPK Inhibitors for the treatment of leukemia

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $331,069

## Abstract

PROJECT SUMMARY
Despite advances in the treatment of acute myeloid leukemia (AML), only 20–30% of patients achieve long-term
disease-free survival (DFS) and treatment options for relapsed AML are extremely limited. The recurrence of
AML has been attributed to leukemic stem cells (LSCs) and efforts are now focused on targeting this drug
resistant population of cells in order to “cure” AML. Our studies measuring energy metabolism in primary human
AML specimens, using reactive oxygen species (ROS) as an indicator of metabolic activity, revealed that LSCs
preferentially reside in a ROS-low state. Furthermore, high levels of activated 5' AMP-activated protein kinase
(AMPK), a central regulator of metabolic pathways, were detected in the LSCs and that knockdown of AMPK
resulted in increased ROS levels and concomitant loss of LSCs. Based on these findings, we propose that AMPK
inhibition will leverage LSCs out of the ROS-low state decreasing their viability which may be sufficient for LSC
elimination or may sensitize them to conventional therapy. There are few potent and selective AMPK inhibitors;
however, the multi-kinase inhibitor sunitinib has been reported as a potent inhibitor of AMPK kinase activity.
Therefore, the central goal of our research is to develop potent and selective oxindole-based AMPK-targeted
agents and examine the effect of AMPK inhibition or degradation in AML models. We have developed an initial
series of oxindoles and although we identified potent AMPK inhibitors from this initial series, we believe further
AMPK selectivity and inhibitory potency is possible. We will use computational-based modeling to guide the
development of inhibitors and evaluate their AMPK inhibitory activity using in vitro kinase assays. Then, inhibition
of cellular AMPK will be determined by measuring the phosphorylation of the AMPK substrate acetyl-CoA
carboxylase (ACC) by ELISA in MOLM13 and MOLM14 cells, and select inhibitors will be submitted for kinome
profiling (Aim 1). AMPK inhibitors that retain an aminoalkyl side-chain extending out of the ATP-binding site will
be coupled to a proteolysis targeting chimera (PROTAC) degrader and their ability to degrade cellular AMPK will
be evaluated. The oxindole-based AMPK inhibitors or degraders that have a terminal dimethylamino group that
interacts with the DFG motif of AMPK will be modified to incorporate a nitroimidazole hypoxia-activated prodrug
moiety that are designed to introduce a tier of LSC selectivity (Aim 2). The effect of AMPK inhibitors and PROTAC
degraders on cell viability, metabolism and ROS levels as single agents will be determined in MOLM13 and
MOLM14 cells and in primary AML cells, LSCs, and normal hematopoietic stem cells (HSCs). Then, the effect
of AMPK inhibitors or degraders in combination with venetoclax will be determined in MOLM13 and MOLM14
cells and in primary AML cells. Finally, the effect of our AMPK inhibitors or degraders as single agents and in
combination with venetoclax wil...

## Key facts

- **NIH application ID:** 10438847
- **Project number:** 5R01CA251534-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Philip Reigan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $331,069
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438847

## Citation

> US National Institutes of Health, RePORTER application 10438847, Development of AMPK Inhibitors for the treatment of leukemia (5R01CA251534-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10438847. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*