# Targeted Small Molecule Inhibitors for Inv(16) Leukemia

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $675,954

## Abstract

The gene encoding CBFβ (CBFB) is disrupted by the chromosome 16 inversion [inv(16)(p13q22)],
associated with ~10% of acute myeloid leukemia (AML) in humans, resulting in a transcription factor fusion
protein containing most of CBFβ fused to the coiled-coil tail region of smooth muscle myosin heavy chain
(SMMHC). The CBFβ-SMMHC fusion protein acts as a dominant repressor of CBF function, binding RUNX1 and
dysregulating the expression of multiple genes required for normal hematopoiesis. Current treatment utilizing
cytotoxic chemotherapy results in 55% five year overall survival but only 17% for older patients. These data
clearly indicate that targeted therapies that can improve the therapeutic response for inv(16) AML patients,
particularly those who have relapsed or are at risk of relapse, is essential. Emerging literature suggests that
inability to cure cancers with current therapies may be attributed to a population of cancer stem cells or cancer
initiating cells that have long term self-renewal potential and can fully recapitulate tumor phenotype at time of
relapse. Inv(16) AML is a good example of this failure because inv(16) patients invariably show, at time of
relapse, the inv(16) rearrangement, while other mutations detected at diagnosis (RAS, FLT3ITD, or KIT) may or
may not be detected. Our hypothesis is that small molecule inhibitors of the binding of CBFβ-SMMHC to RUNX1
could be effective therapeutic drugs that eradicate the leukemia initiating cell population in inv(16) leukemia,
thereby achieving better long term survival. Recently we developed a first generation inhibitor which targets the
protein-protein interaction between CBFβ-SMMHC and RUNX1. In this application, we are proposing two aims:
 Aim 1: Optimization of CBFβ-SMMHC inhibitors for improved potency and ADMET properties. We
propose to modify our first generation inhibitor to improve ADMET properties to develop a potent orally
bioavailable inhibitor for the treatment of inv(16) leukemia. Specifically, we propose to modify the structure of the
linker by substitution of five-membered heterocycle based linkers in the bivalent inhibitors we have developed to
improve the solubility and the oral bioavailability of the inhibitor. The most promising compounds will be profiled
for pharmacokinetic properties in mice and rats, as well as using a panel of in vitro ADMET properties. The most
promising compounds will be tested in Aim 2 for in vivo efficacy and efficacy against inv(16) patient samples.
 Aim 2: Characterization of promising CBFβ-SMMHC inhibitors using AML patient cells and mouse models
for inv(16) AML. We propose to determine the efficacy and specificity of the most promising inhibitors in reducing
the survival of inv(16) AML compared to non-inv(16) AML patient samples in vitro. We also propose to determine
their efficacy in mice, utilizing in vivo treatment in a genetically engineered model (GEM) and a patient-derived
xenograft (PDX) mouse model for inv(16) acute myeloid le...

## Key facts

- **NIH application ID:** 9817687
- **Project number:** 5R01CA234478-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** JOHN Hackett BUSHWELLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $675,954
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9817687

## Citation

> US National Institutes of Health, RePORTER application 9817687, Targeted Small Molecule Inhibitors for Inv(16) Leukemia (5R01CA234478-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9817687. Licensed CC0.

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