# Novel Small-Molecule Probes Targeting Oncogenic Fusion MLL in Pediatric Leukemia

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $437,571

## Abstract

Acute leukemia, including acute myeloid (AML) and lymphoid leukemia (ALL), is the most common (1 out of 3)
cancer in children and adolescents. Particularly, leukemia caused by chromosome translocations involving
mixed lineage leukemia (MLL) gene accounts for ~75% of leukemia in infants and ~10% in children/adults with
a poor prognosis. Compared to other pediatric ALL with a 5-year survival of ~90%, that for MLL-rearranged
ALL is only ~40%, and for very young infants, the survival is even <20%. MLL-rearranged AML patients have
similarly poor clinical outcomes to other AMLs. Current treatments are conventional chemo-drugs, which kill all
rapidly proliferating cells including normal stem cells in bone marrow and other organs. This causes severe
toxicities, side effects, and even secondary cancer due to mutagenesis. There is therefore a pressing need to
find less toxic drugs targeting MLL-oncogene that drives the malignancy. MLL-oncogene consists of MLL fused
with another gene. AF9 (~30%) and AF4 (35%) are the most frequent fusion partners of MLL. These proteins,
together with DOT1L (a known drug target for the leukemia), associate with each other and constitute the so-
called super elongation complex (SEC), which causes malignant gene expression in leukemia. Previous
studies show the protein-protein interactions between AF9 and AF4 or DOT1L is critical to MLL-leukemia, but
is dispensable in normal cells. This project aims to find and develop the first small-molecule inhibitors that
disrupt the AF9-AF4/DOT1L interaction, which could be novel chemical probes for biological studies of
AF9/SEC, or potential therapeutics for MLL-rearranged leukemia with a low toxicity. The Specific Aim 1 is to
use rational design and medicinal chemistry to find potent, drug-like inhibitors of AF9. Aim 2 is to perform
biochemical, X-ray and NMR structural studies to characterize inhibitor-AF9 interactions. Aim 3 is to perform
cell-based assays to test biological activities of selected potent inhibitors, and Aim 4 is to perform
pharmacokinetics, toxicity, and antitumor activity testing to identify useful chemical probes or potential drug
candidates.

## Key facts

- **NIH application ID:** 10340987
- **Project number:** 1R01CA266057-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Yongcheng Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $437,571
- **Award type:** 1
- **Project period:** 2021-12-10 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10340987

## Citation

> US National Institutes of Health, RePORTER application 10340987, Novel Small-Molecule Probes Targeting Oncogenic Fusion MLL in Pediatric Leukemia (1R01CA266057-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10340987. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*