# A Chemical Genetic Approach to Exploring Novel Therapeutic Space for Colorectal Cancer

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $635,077

## Abstract

Project Summary
Metastatic colorectal cancer (mCRC) is the second leading cause of cancer-related mortality in the United
States, and annually accounts for nearly 500,000 deaths worldwide. Currently, the small molecule kinase
inhibitor (KI) regorafenib is the primary second line therapy for metastatic CRC that is not treatable with
immunotherapy or anti-EGFR therapies. However, regorafenib generally provides only modest improvements in
survival— typically months—and often at the cost of significant side effects. Proposed targets for regorafenib
include kinases that act within tumor cells as well as non-autonomously; however, with over 500 possible targets
in the human kinome, the exact mechanism by which this compound operates remains controversial and not
fully known. This presents a daunting challenge; without a verifiable target or mechanism, no clear path exists
to guide the development of improved therapies for mCRC.
 Here, we propose an alternative approach to drug development that focuses on kinase networks in the
context of the whole animal. Specifically, we will take a multidisciplinary approach to define kinases that are
beneficial to inhibit (‘pro-targets’) or avoid (‘anti-targets’) in the context of KRAS-variant CRC. Using Drosophila
and mammalian models, we will identify kinases that—when reduced—alter the efficacy of regorafenib and
similar compounds. We will also conduct extensive structure-activity relationship analyses, evaluating how
modifications in already identified lead compounds impact changes in efficacy and therapeutic index. Finally, we
will use computational structural biology to convert our chemical genetic insights into highly optimized and
precise polypharmacological leads. In this final step, we generate new analogs to selectively eliminate putative
anti-target activity while maintaining or increasing inhibitory activity against other beneficial targets.
 We have used our chemical genetic platform to identify a promising lead compound, APS5-86-2, that
demonstrates significant activity relative to regorafenib in several mCRC models, including human patient
derived xenografts (PDX). Comparative analysis suggests that the improved activity of APS5-86-2 relative to
regorafenib derives from distinct polypharmacology on several RTKs and critical cancer drivers, including CDK9,
AURKA, EGFR, BRAF, and RAF1. In this proposal, we examine the mechanism and importance of these and
other putative pro- and anti-target kinases using genetic analysis and in vivo target engagement. The objective
is to identify the kinase networks that mediate KRAS-variant mCRC by combining chemical biology with genetics,
and to then derive inhibitors that best attack these networks through structure-based drug design. We have been
successful previously with a similar approach, but in less complex tumor models (Dar et al., Nature, 2012;
Sonoshita et al., Nature Chem. Bio., 2018); here we seek to extend our platform to a more prevalent disease
with th...

## Key facts

- **NIH application ID:** 10182641
- **Project number:** 1R01CA258736-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ross Leigh Cagan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $635,077
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10182641

## Citation

> US National Institutes of Health, RePORTER application 10182641, A Chemical Genetic Approach to Exploring Novel Therapeutic Space for Colorectal Cancer (1R01CA258736-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10182641. Licensed CC0.

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