# Activation and Regulation Mechanisms of the RAF Kinase Family

> **NIH NIH R01** · ROWAN UNIVERSITY · 2024 · $70,209

## Abstract

BRAF, a member of the RAF family protein kinases, works in the MAPK signaling pathway, which controls broad
cellular events like proliferation and differentiation. BRAF is the most frequently mutated kinase in human
cancers. Furthermore, tumors lacking BRAF mutations are contingent on BRAF activity when there are mutations
in upstream pathway members, such as RAS or growth factor receptors. Thus, BRAF represents an important
target for cancer therapy. Despite three decades of intense research, only recently has a sufficient understanding
of BRAF's mechanism creaked open the door to BRAF therapy. However, the current clinical BRAF inhibitors,
vemurafenib and dabrafenib, are limited to the class I mutant BRAFV600E. Vemurafenib and dabrafenib, the two
ATP-competitive inhibitors, can paradoxically activate non-BRAFV600E and wild-type BRAF, suggesting that
BRAF has functions that are independent of its kinase activity. Therapeutic strategies for tumors with non-
BRAFV600E mutations and wild-type BRAF are still lacking. Gaps in our knowledge contributed to the limitations
of ATP-competitive BRAF drugs. The proposed work centers around three questions regarding RAF activation
and regulation in health and disease states. Q1: how BRAF structural elements and ATP binding mediate the
catalytic-independent functions of non-BRAFV600E and wild-type BRAF? Q2: what is the mechanism of action of
the first BRAF allosteric inhibitor developed by our group and how can inhibitors targeting the catalytic and non-
catalytic functions of BRAF be developed? Q3: What factors contribute to the non-overlapping functions of RAF
isoforms, despite their structural similarity? The PI and her team will address these questions through
multidisciplinary approaches, including X-ray crystallography, binding kinetics, phosphoproteomics, live cell
imaging, chemical biology, and computational methods. Our findings will not only facilitate a better understanding
of the complex biochemical mechanisms of the RAF kinase family, also provide a molecular basis for novel
therapeutic approaches targeting BRAF-driven tumors.

## Key facts

- **NIH application ID:** 11100231
- **Project number:** 3R01GM138671-04S1
- **Recipient organization:** ROWAN UNIVERSITY
- **Principal Investigator:** Zhihong Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $70,209
- **Award type:** 3
- **Project period:** 2021-09-10 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100231

## Citation

> US National Institutes of Health, RePORTER application 11100231, Activation and Regulation Mechanisms of the RAF Kinase Family (3R01GM138671-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11100231. Licensed CC0.

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