# Targeting defective spliceosomal pathway in myeloid malignancies

> **NIH NIH R21** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $231,699

## Abstract

Abstract
Whole-exome and targeted sequencing of MDS patients’ samples have led to discover a set of genes (SF3B1,
U2AF1, SRSF2, ZRSR2 and LUC7L2) encoding mutant RNA splicing factors that alter expression patterns of
protein isoforms in clonal evolution of hematopoietic cells during MDS progression. Subsequent studies found
occurrences of these splicing factor mutations in AML and solid tumors. Clinical data also showed
heterozygous missense mutations or hemizygous deletions of these genes are mostly mutually exclusive
implying that mutations in multiple proteins in splicing regulation may be lethal in MDS cells. To date, only one
compound, H3B-8800, to target SF3B1 is in phase I clinical trial to treat MDS and other myeloid malignancies.
No agents targeting other mutated splicing factors are in pre-clinical development and if other mutant factors
can be potential drug targets is unknown. Among them, U2AF1 mutations occurred in early MDS clones and
are poor prognostic features for progression to leukemia. Studies showed U2AF1S34F hematopoietic cells and
transgenic mouse models are sensitive to sudemycin that targets SF3B1. Recently, U2AF1wt was suggested to
be a haplo-essential gene for the survival of cancer cells containing U2AF1 mutation. Our central hypothesis is
that U2AF1wt inhibition may induce synthetic lethality to U2AF1S34F clones that depends on U2AF1wt for
survival. Our rationale is that blockade of U2AF1/U2AF2 association may impair U2AF1wt function. Using
fragment-based library screening, we have identified a hit compound that inhibited the U2AF1/U2AF2 binding
and exhibited selective growth inhibition in K562-U2AF1S34F and human primary cells carrying U2AF1
mutations but not their wild-type counterparts. Our objective of this proposal is to develop a new class of
U2AF1 inhibitors based on the hit and assess the therapeutic concept of synthetic lethality in MDS/AML
disease models. Our long-term goal is to develop small-molecule therapeutics to target cancer cells defective
in the spliceosome pathway. To achieve our goal, we have devised two specific aims: 1) Optimization of
U2AF1 inhibitors by integrating computer-aided design with chemical syntheses; 2) Study the therapeutic
effects of U2AF1 inhibitors using in vitro and in vivo U2AF1mut MDS/AML models. In Aim 1, we will improve the
activity and selectivity of U2AF1 inhibitors based on the preliminary structure activity relationship and selectivity
data of SF1-8 by integrating chemical syntheses, computer-aided design, biochemical assays and the co-
crystal structure determination. In Aim 2, we will assess the activities of our U2AF1 inhibitors in MDS/AML
cellular models, analyze transcriptome and splicing pattern changes in cell lines treated with U2AF1 inhibitors
and determine the effects of our inhibitors on erythropoiesis in xenograft mouse models. Our application is
innovative and significant, because it builds on our discovery of the hit to U2AF1, an emerging novel target
asso...

## Key facts

- **NIH application ID:** 10434248
- **Project number:** 1R21CA270590-01
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** VALERIA VISCONTE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $231,699
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434248

## Citation

> US National Institutes of Health, RePORTER application 10434248, Targeting defective spliceosomal pathway in myeloid malignancies (1R21CA270590-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10434248. Licensed CC0.

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