# Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent

> **NIH NIH R42** · PACDNA LLC · 2022 · $400,000

## Abstract

Project Summary/Abstract
 Mutant forms of KRAS are a key driver in human tumors but remain partially refractory to therapeutic
intervention. After over three decades of research, only a single inhibitor (sotorasib) targeting a single
mutation (KRASG12C) have reached market. The difficulty for developing small molecule KRAS inhibitors
has heightened the importance of alternative methods targeting the oncogene. One such strategy
involves therapeutic nucleic acids, which make it possible to deplete target proteins that are intractable to
conventional drug modalities. We have developed a novel form of nucleic acid therapeutics, termed
Brushield™ conjugate, which substantially enhances the antitumor activity of antisense oligonucleotides
by elevating in vivo stability, accelerating cellular uptake, and improving plasma pharmacokinetics and
tumor accumulation, allowing for a much lower dosage to be used compared to conventional methods.
The conjugate also suppresses nearly all side effects associated with traditional nucleic acid drugs by
reducing unwanted nucleic acid-protein interactions. The goal of this proposal is to lay the groundwork
for translating the technology towards the clinic. In Phase I, we will optimize the structure of the
Brushield™ conjugate, and enhance current indication using a panel of non-small cell lung cells and
mouse xenograft models. Upon reaching set quantitative milestones, we will subject the conjugate to
more relevant animal models (orthotopic and patient-derived xenograft models), and perform tolerability
and pharmacokinetic studies in mice and monkeys (Phase II). These studies will allow us to pursue an
IND filing at the end of the project.

## Key facts

- **NIH application ID:** 10544115
- **Project number:** 1R42CA275425-01
- **Recipient organization:** PACDNA LLC
- **Principal Investigator:** Ke Zhang
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,000
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10544115

## Citation

> US National Institutes of Health, RePORTER application 10544115, Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent (1R42CA275425-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10544115. Licensed CC0.

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