# Chemical biological analysis of RAF Kinases

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $508,660

## Abstract

Abstract
The serine/threonine Raf Kinases function as downstream modulators of RAS GTPase-driven signaling and are
key drivers of many oncogenic signaling networks. Despite extensive efforts to characterize the molecular
functions of Raf kinases and to develop pharmacological modulators as cancer therapies, many aspects of Raf
kinase regulation and intracellular function are not well understood. Recent work suggests that the interplay of
different Raf isoforms (A/B/C-R Raf) can have a profound effect on downstream signaling and may be a major
determinant in the ability to pharmacologically target cancers that are driven by mutant RAS and Raf. Here, we
propose a systematic biochemical analysis of Raf regulation, intracellular function, and pharmacology.
Leveraging a suite of molecular tools for dissecting the “druggability” of RAF isoforms, we will define pathways
that make Raf kinases sensitive or resistant to specific classes of ATP-competitive inhibitors and co-inhibition
strategies. In addition, by applying a new RNA barcoding methodology that we’ve developed, we will perform
deep mutational scans of the structure, function, and pharmacology of Raf isoforms. Furthermore, we will
systematically analyze how upstream and downstream modulators of Raf kinase signaling affect the activity and
intracellular interactions of Raf kinases. Together, these studies will provide a more complete picture of Raf
kinase regulation, intracellular function, and may facilitate more effective therapeutic targeting of RAS- and Raf-
driven cancers.

## Key facts

- **NIH application ID:** 10995941
- **Project number:** 1R01CA290740-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Dustin J Maly
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $508,660
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995941

## Citation

> US National Institutes of Health, RePORTER application 10995941, Chemical biological analysis of RAF Kinases (1R01CA290740-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10995941. Licensed CC0.

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