# Chemical manipulation of creatine kinases to treat acute myeloid leukemia

> **NIH NIH R21** · DANA-FARBER CANCER INST · 2021 · $450,655

## Abstract

PROJECT SUMMARY:
Over the last decade, essential metabolic dependencies of many cancers have been revealed. These
dependencies have highlighted that certain nodes of metabolism are attractive drug targets to drive cancer
cell death. For the most part, oncogenic metabolic proteins have not been drugged, and many lack obvious
binding pockets for pharmacological manipulation. Among the most prominent examples of un-drugged
metabolic cancer targets are creatine kinases (CKs). CKs are essential for growth and metastasis of
numerous cancers, especially aggressive acute myeloid leukemias (AML). The essentiality of CKs for
aggressive AMLs is distinct, as somatic tissues do not rely on CKs for viability. However, despite being a
highly actionable drug target in AML, no potent inhibitors exist against CKs.
We recently developed a mass spectrometric (MS) platform that allows for rapid screening of small
molecules for covalent engagement with protein cysteines across the proteome. With preliminary data, we
have combined this platform with a small molecule screening library to systematically identify drug leads
targeting cysteines on un-drugged proteins. In doing so, we have identified a lead scaffold that is potently
inhibitory against the CK family of enzymes, by selectively targeting a key active site cysteine residue.
Moreover, at high nanomolar concentrations, this CK inhibitor is selectively cytotoxic to AML cancers that
depend on CKs. The goal of this project is to develop this new scaffold class of CK inhibitor for clinical
application in AML cancers. We will test the hypothesis that rational development of this scaffold will improve
potency and AML toxicity by targeting key interactions at the CK active site pocket. Moreover, we will
determine whether this new CK inhibitor class is an effective therapeutic in a mouse model of AML in vivo.
In Aim 1 we will combine molecular modeling approaches and our preliminary SAR data to rationally develop
a series of molecules to systematically probe inhibitory potency against the CK active site pocket. Activity
and selectivity of these molecules will be determined using our MS platform, isolated CK kinetics, and
cellular AML models. In parallel, using patient-derived cellular models of AML, for which CK is essential, we
will determine clinically relevant disease-modifying outputs, including viability, colony forming, and on-target
toxicity. In Aim 2 we will determine therapeutic efficacy of our CK inhibitor chemotype in mouse models
EVI1-positive AML that rely essentially on CKs. Taken together, this project will advance a first-in-class
inhibitor of CKs, which is an un-drugged metabolic dependency of AML cancers. Successful completion of
these Aims would position this new chemotype for treatment of AML, and provide a new chemical probe for
understanding the role CKs play in AML and cellular metabolism.

## Key facts

- **NIH application ID:** 10198222
- **Project number:** 1R21CA259739-01
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Edward Thomas Chouchani
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,655
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198222

## Citation

> US National Institutes of Health, RePORTER application 10198222, Chemical manipulation of creatine kinases to treat acute myeloid leukemia (1R21CA259739-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10198222. Licensed CC0.

---

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