# The Development of First-in-Class Inhibitors of Oncogenic CHD1L for the Treatment of Colorectal Cancer.

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $354,514

## Abstract

Colorectal cancer (CRC) is the third most prevalent type of cancer diagnosed each year and CRC patients have
the second highest mortality rate, worldwide. Standard of care treatments for CRC is largely ineffective against
metastatic CRC (mCRC), which has an 11% 5-year overall survival rate. Aberrant T-Cell Factor (TCF)
transcription is a major driver of tumor progression to mCRC. Therapeutic development directly targeting the
inhibition of TCF-transcription of genes associated with mCRC may be an effective therapeutic strategy for
mCRC, and currently no such therapies are clinically approved. Using a cohort of ~600 CRC patient tumor
samples (GEOdataset (GSE40967) and CU AMC GI tissue bank), we have identified an oncogene, known as
CHD1L, to be linked as a driver of mCRC and patient poor prognosis. We have characterized CHD1L to be a
required component of TCF-transcription during malignant gene expression. We hypothesize that CHD1L is a
molecular target that functions as a DNA binding factor for the TCF-transcription complex, and CHD1L is
specifically recruited to activate mesenchymal genes and other genes associated with mCRC. Currently there
are no known inhibitors of CHD1L. Thus, we conducted HTS drug discovery targeting recombinant CHD1L
ATPase to identify the first-in-class inhibitors of CHD1L. In Aim 1 we will validate these CHD1L inhibitors as
lead drugs using a hit-to-lead schema in sequence. In Aim 2 we will conduct drug design and medicinal chemistry
based on a validated lead CHD1L inhibitor pharmacophore. In Aim 3 we will prioritize 15 lead CHD1L inhibitors
for in vivo pharmacology, including pharmacokinetics, pharmacodynamics, and efficacy in patient derived
xenografts. This research will lead to a diversity of novel CHD1L inhibitors that can be developed as molecular
probes or potential therapeutics that would be expected to impact our understanding and treatment of mCRC.

## Key facts

- **NIH application ID:** 10034352
- **Project number:** 1R01CA251361-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Daniel V. LaBarbera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,514
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10034352

## Citation

> US National Institutes of Health, RePORTER application 10034352, The Development of First-in-Class Inhibitors of Oncogenic CHD1L for the Treatment of Colorectal Cancer. (1R01CA251361-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10034352. Licensed CC0.

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