# Discovery of MAP2K7 Inhibitors Through DNA-Encoded Chemical Screens to Treat T-Cell Acute Lymphoblastic Leukemia

> **NIH NIH R21** · BAYLOR COLLEGE OF MEDICINE · 2024 · $412,685

## Abstract

Project Summary
Acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy. The disease incidence peaks
in children younger than five, declining until the mid-20s and increasing after age 50. Despite advances in treating
pediatric patients, at least one out of five children relapse and die of leukemia. T-cell ALL (T-ALL) presents a
higher risk for relapse than the B-cell ALL subtype, and relapse disease is a significant cause of cancer-related
deaths in children. Children with leukemia exhibiting an increased risk of treatment failure and relapse
desperately need an alternative therapy to induce durable remission. However, developing alternative treatments
requires identifying actionable pro-leukemic pathways in leukemic cells, particularly in drug-resistant leukemic
cells able to reinitiate disease and cause relapse. We are well-positioned to fulfill this medical need because we
recently identified aberrant activation of the kinase MAP2K7 in bulk T-ALL leukemic cells and the leukemia-
initiating cell (LIC) population involved in refractory and relapsed disease. In the absence of potent and specific
inhibitors of MAP2K7, we showed as a proof of concept that leukemic cells are vulnerable to pharmacological
JNK inhibition, the sole downstream target; however, low potency and off-target toxicity prevent translating JNK
inhibitors to the clinics. Based on these findings, we hypothesize that direct targeting with novel MAP2K7
inhibitors can increase treatment response by eradicating chemoresistant leukemic cells. In this application, we
propose developing targeted inhibition of the aberrantly activated MAP2K7 pathway through the screen of
MAP2K7 protein binders using DNA-encoded chemical libraries (Aim 1) and studying kinase inhibitory activity
and efficacy of identified inhibitors in pre-clinical mouse models to accelerate clinical translation in T-ALL patients
(Aim 2). To achieve this goal, we assembled a collaborative team composed of a research scientist with expertise
in genetic and xenograft mouse models to study T-ALL, a physician-scientist involved in clinical trials at the
Texas Children's Hospital, and a medicinal chemist at the Center for Drug Discovery at Baylor College of
Medicine. The proposed study can result in new therapies to target a novel target to treat pediatric patients with
high-risk leukemia.

## Key facts

- **NIH application ID:** 10947327
- **Project number:** 1R21CA286412-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Daniel Lacorazza
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $412,685
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10947327

## Citation

> US National Institutes of Health, RePORTER application 10947327, Discovery of MAP2K7 Inhibitors Through DNA-Encoded Chemical Screens to Treat T-Cell Acute Lymphoblastic Leukemia (1R21CA286412-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10947327. Licensed CC0.

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