# Ligand-Directed KRAS G12V Mutant-Specific Therapeutics

> **NIH NIH R44** · ENFUEGO THERAPEUTICS INC. · 2024 · $919,020

## Abstract

Project Summary
 The proto-oncogene KRAS is one of the most critical genes in cancer, yet, as a drug target, it has proven
to be among the most elusive. A remarkable 30% of lung adenocarcinomas, 45% of colon, and 98% of pancreatic
cancers are driven by KRAS mutations. These cancers account for the top 3 causes of cancer-related
deaths in the United States. Most cancer associated KRAS mutations result in a constitutively active protein,
which drives aberrantly high downstream signaling of pro-proliferative and pro-survival effectors including the
MAPK and PI3K pathways. Kinase inhibitors have revolutionized treatment of many cancers driven by other
molecular aberrations, yet, unfortunately a lack of such success in KRAS-driven cancers has led to KRAS
itself to be widely regarded as “undruggable”. EnFuego Therapeutics, Inc. (EFTX) was founded to address
the growing number of “undruggable” targets in cancer using RNA interference (RNAi)-based therapeutics. RNAi
is particularly attractive for KRAS targeting because it can be optimized to enable selective silencing of mutant
transcripts while sparing wild type transcripts, which is important for maintaining normal function in nonmalignant
tissue. Mutation-specific therapeutics against KRAS are under development by several companies such as
Amgen and Mirati, and rely on small molecules (specific only to G12C mutations). Unlike prior RNAi strategies
in cancer, the EFTX approach employs nucleotide modification and ligand conjugation chemistries to promote
in vivo stability and affinity-based targeting in cancer cells. In particular, ligand conjugation represents a
significant advantage over legacy delivery technologies such as lipid nanoparticles. We have shown that
EnFuego siRNAs targeting mutant KRAS transcripts result in: 1) reduced oncogenic MAPK signaling, 2) reduced
cancer cell proliferation, and 3) reduced tumor burden in murine cancer models. Based on these preliminary
data, this Fast Track program will further develop EFTX siRNA technologies for targeting mutant KRAS in
humans. During Phase I, we will focus on optimization of fully chemically modified (FM) siRNA compounds that
potently and specifically silence mutant G12V transcripts, exhibit serum stability and immune stealth, and inhibit
downstream cancer cell signaling. Two to three FM siRNAs will be selected as lead compound candidates for
progression to Phase II studies. Phase II Specific Aims will focus on optimization of pharmacokinetics, tissue
targeting, and efficacy in murine models of metastatic lung cancer. These data will inform the selection of a single
candidate for scale up and a 4-week GLP safety assessment study. As such, this Fast Track program will
accelerate progression of this novel therapeutic strategy toward filing an Investigational New Drug application
for metastatic lung cancer therapy.

## Key facts

- **NIH application ID:** 11116069
- **Project number:** 4R44CA284932-02
- **Recipient organization:** ENFUEGO THERAPEUTICS INC.
- **Principal Investigator:** Chad V Pecot
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $919,020
- **Award type:** 4N
- **Project period:** 2023-07-05 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11116069

## Citation

> US National Institutes of Health, RePORTER application 11116069, Ligand-Directed KRAS G12V Mutant-Specific Therapeutics (4R44CA284932-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11116069. Licensed CC0.

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