# Structure, mechanism, and pharmacology of BRAF and its partners in the RAS/RAF/MAP kinase pathway

> **NIH NIH R35** · DANA-FARBER CANCER INST · 2021 · $1,068,000

## Abstract

Abstract
 The RAS/MAP kinase pathway is aberrantly activated in a wide variety of human cancers. The V600E
mutation in BRAF, a kinase in this pathway, causes approximately one-half of all melanomas and is the driver in
many other cancers as well. Despite decades of intense interest and investigation, BRAF regulation is not well-
understood. Furthermore, compounds targeting the RAS/MAPK pathway exhibit poorly understood
pharmacologic effects. BRAF inhibitors, such as vemurafenib, potently inhibit V600E BRAF, but they
paradoxically activate wild type BRAF. Inhibitors of MEK, a kinase downstream of BRAF, differ in their efficacy
depending upon whether the pathway is activated by mutations in KRAS versus BRAF. Collectively, the
confusing pharmacology of these agents reflects our incomplete knowledge of the regulation and biochemical
workings of this pathway and limits our ability to develop targeted therapies for BRAF and the RAS/MAPK
pathway.
 Over the last two decades, my laboratory has focused on the structural biology of protein kinases and
their dysregulation in cancer, and on cancer drug discovery. We have applied our basic biophysical, biochemical
and structural insights into wild-type and mutant EGFR to discover new classes of pharmacologic agents
targeting the mutant receptor, including both mutant-selective covalent and allosteric inhibitors that can
overcome resistance mechanisms. We are now applying an analogous structural and mechanistic approach to
demystify BRAF regulation and pharmacology. Our objectives are to understand BRAF regulation in structural
detail, to decipher the complex pharmacology of the BRAF and MEK inhibitors, and to develop new agents that
target the pathway in a mutant-selective manner. To achieve these goals, we will determine the structure of
autoinhibited and active BRAF complexes using cryo-electron microscopy. We will reconstitute the pathway from
KRAS to ERK using purified components in order to dissect mechanisms of BRAF and MEK activation and probe
the effects of pharmacologic agents that target the pathway. In addition, we will use these reconstitutions together
with our structural insights to discover new agents that target the pathway in a mutant-selective manner. These
studies will provide fundamental new understanding of BRAF regulation and, in the long term, they should yield
more effective and better tolerated therapies for cancers driven by mutagenic activation of this pathway.

## Key facts

- **NIH application ID:** 10212985
- **Project number:** 5R35CA242461-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** MICHAEL J ECK
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,068,000
- **Award type:** 5
- **Project period:** 2019-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212985

## Citation

> US National Institutes of Health, RePORTER application 10212985, Structure, mechanism, and pharmacology of BRAF and its partners in the RAS/RAF/MAP kinase pathway (5R35CA242461-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212985. Licensed CC0.

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