# Development of novel anti-leukemia agents targeting the menin-MLL interaction

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $372,809

## Abstract

Chromosomal translocations of the Mixed Lineage Leukemia 1 (MLL1) gene that result in expression of MLL
fusion proteins are found in about 10% of acute leukemias affecting both children and adults. Patients
harboring MLL fusions have very poor prognosis, with only ~35% five-year survival rate, implying the need for
development of new therapies. The MLL fusion proteins retain the N-terminal fragment of MLL, while the C-
terminal portion is replaced by one out of 60 fusion partners leading to a variety of MLL fusions. Importantly, all
MLL fusion proteins interact with menin, a protein encoded by the Multiple Endocrine Neoplasia 1 (MEN1)
gene, and the menin-MLL fusion protein interaction is critical to the oncogenic activity of MLL fusions in
leukemia. Indeed, the menin-MLL interaction has been validated in the pre-clinical models as a valuable
molecular target for development of new therapies for MLL leukemia. We hypothesize that inhibition of the
menin-MLL fusion protein interaction by small molecules should reverse oncogenic activity of MLL fusion
proteins and inhibit progression of MLL leukemia in vivo, resulting in a new targeted therapy for MLL leukemia
patients.
 To this end we developed small molecule inhibitors of the menin-MLL inhibitors, which represent the
first small molecules reported to block this protein-protein interaction. These compounds directly binding to
menin at the MLL binding site and strongly inhibit the menin-MLL interaction. We substantially optimized both
potency and drug-like properties of these compounds, resulting in very potent menin-MLL inhibitors (IC50 < 15
nM, Kd < 10 nM). In MLL leukemia cells, these compounds selectively inhibit proliferation, induce differentiation
and downregulate expression of MLL fusion target genes at nanomolar concentrations. Importantly, the menin-
MLL inhibitors we developed (e.g. MI-503, MI-463) markedly block progression of leukemia in vivo in mice
models of MLL leukemia. In this project we will continue optimization of menin-MLL inhibitors to further improve
their potency and drug-like properties with the goal to develop compounds with very strong in vivo efficacy in
aggressive models of MLL leukemia, including patient derived xenografts (PDX). We will also study optimal
combinations of menin-MLL inhibitors with selected chemotherapy and targeted agents to identify the best
combinations for future clinical studies. Furthermore, we will investigate whether resistance develops to the
treatment with menin-MLL inhibitors. This work should result in very potent and selective menin-MLL inhibitors
that may provide a novel therapeutic approach for the treatment of MLL leukemia patients.

## Key facts

- **NIH application ID:** 10131136
- **Project number:** 5R01CA160467-10
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jolanta Grembecka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,809
- **Award type:** 5
- **Project period:** 2011-09-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131136

## Citation

> US National Institutes of Health, RePORTER application 10131136, Development of novel anti-leukemia agents targeting the menin-MLL interaction (5R01CA160467-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10131136. Licensed CC0.

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