# Development of novel selective Rac inhibitors for refractory leukemias

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $585,986

## Abstract

Project summary/abstract
Rac belongs to the family of Rho GTPases, proteins that regulate critical cellular
functions by integrating extracellular signals and coordinating activation of downstream
effectors. In several models of leukemia (BCR-ABL, MLL-rearranged and RAS-mutated
leukemia), Rac is aberrantly activated and its genetic deletion can attenuate the
transforming effect of driver oncogenes. Moreover, increased activation of Rac due to
the expression of an alternative splicing version or to mutations in its coding sequence
has been shown to play a critical role in the malignant progression of some solid tumors,
including breast, lung and colon cancer as well as melanoma. Due to its biochemical
properties, Rac has not been fully exploited as a therapeutic target in cancer. However,
a tool compound (NSC 23766) that inhibits Rac activation at high concentration in
mammalian cells has been previously developed and inhibits malignant transformation
mediated by BCR-ABL in vitro and in vivo.
In the present project, the Williams laboratory, a leader in Rho GTPase biology in
hematopoietic stem cells, is partnering with Evotec (a medicinal chemistry company with
deep expertise in drug discovery) to carry out orthogonal approaches to develop small
molecule inhibitors of Rac for the treatment of refractory leukemias (in particular, MLL-
rearranged and RAS-mutated). We propose the following approaches to identify new
inhibitors and develop recently identified compounds into lead molecules:
1) Optimization of DW_0069, the lead compound previously identified by a virtual
 screening for Rac inhibitors. This compound inhibits Rac activation in vitro and in
 vivo, and is well tolerated in leukemia xenograft models. We have already identified
 several analogues with increased potency. In this project, we propose to further
 optimize this compound and to investigate its mechanism of action.
2) Expansion of a fragment-based drug discovery program for Rac inhibitors, and
 development of additional hits identified by a fragment-based NMR screen.
Criteria for prioritization of compound development will involve extended SAR studies,
good absorption, distribution, metabolism, and excretion- (ADME) properties, and activity
in advanced cellular and animal models of RAS-mutated and MLL-rearranged
leukemias. The project proposal includes a timeline for nomination of lead compounds
for human testing and an outline of a proposed phase I human trial.

## Key facts

- **NIH application ID:** 9968142
- **Project number:** 5R01CA202756-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** DAVID A WILLIAMS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $585,986
- **Award type:** 5
- **Project period:** 2016-07-20 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968142

## Citation

> US National Institutes of Health, RePORTER application 9968142, Development of novel selective Rac inhibitors for refractory leukemias (5R01CA202756-05). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9968142. Licensed CC0.

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