# Development of ASH1L inhibitors for acute leukemia

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $544,236

## Abstract

Acute leukemia is a group of diseases associated with various genetic alterations that block differentiation and
increase proliferation of hematopoietic progenitor cells. Acute Myeloid Leukemia (AML) patients have very poor
prognosis with currently available treatments, reflected by a 5-year survival rate of only 27%. Dysregulation of
HOX genes is associated with numerous malignancies, including acute leukemias. In AML high level of HOX
genes, in particular HOXA9, is associated with refractory disease and very poor prognosis, emphasizing the
urgent need for novel therapies. Therefore, small molecules that reduce HOX genes expression might represent
a novel promising treatment strategy for acute leukemia patients. ASH1L (Absent, small or homeotic 1-like) is a
histone methyltransferase, which belongs to the Trithorax group of proteins regulating HOX genes expression.
ASH1L knockdown studies have demonstrated a critical role of ASH1L in development of leukemia's with
translocations of the MLL gene through regulation of HOXA9 and MEIS1 expression. Our own studies have
validated that the SET domain of ASH1L plays a critical role in leukemogenesis, both in the context of MLL-
rearranged leukemias and other high HOXA leukemias. Importantly, Ash1l-deficient mice exhibit no overt
hematopoietic failure in the steady-state conditions. Based on all these findings we believe that the ASH1L SET
domain represents a valid target in acute leukemias with high HOXA expression.
 In this project, we propose to develop small molecule inhibitors of ASH1L histone methyltransferase as
a potential therapeutic strategy for acute leukemias with high HOXA expression. To this end, we identified very
promising class of small molecules that bind to the SET domain of ASH1L and inhibit its enzymatic activity and
substantially optimized their potency, resulting in compounds with nanomolar binding affinities and high
selectivity to ASH1L These compounds inhibit proliferation, induce differentiation and downregulate expression
of HOXA genes in MLL leukemia cells, demonstrating highly specific mode of action. In this project we will
optimize ASH1L inhibitors to further improve their potency and drug-like properties with the goal to develop
compounds suitable for in vivo efficacy studies in AML models. In Aim 1 we will employ medicinal chemistry to
improve potency and drug-like properties, including metabolic stability, cellular permeability and solubility, of the
lead compounds we already identified. In Aim 2 we will carry out extensive characterization of ASH1L inhibitors
in a panel of acute leukemia cells with high and low level of HOXA genes expression to assess their potency,
mechanism of action and specificity. Aim 3 will be devoted to assess the in vivo efficacy of ASH1L inhibitors in
disseminated models of acute leukemia. We expect the outcome of these studies will result in very potent and
selective ASH1L inhibitors that might provide novel therapeutic approach for acute leuk...

## Key facts

- **NIH application ID:** 10740903
- **Project number:** 5R01CA244254-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jolanta Grembecka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $544,236
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740903

## Citation

> US National Institutes of Health, RePORTER application 10740903, Development of ASH1L inhibitors for acute leukemia (5R01CA244254-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10740903. Licensed CC0.

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