7月22日学术报告:Targeting the non-catalytic function of RAF kinases through inhibition of RAF dimerization

2020年07月21日 11:35  点击:[]

主讲人简介:

Academic Appointments:

Associate Professor (Tenured)  2020-present  

University of the Sciences, Philadelphia, PA

Department of Chemistry & Biochemistry

Assistant Professor  2014-2020  

University of the Sciences, Philadelphia, PA

Department of Chemistry & Biochemistry

Postdoctoral Research Fellow      2008-2014

Johns Hopkins University School of Medicine, Baltimore, MD  

Department of Pharmacology and Molecular Sciences

Advisor: Philip A. Cole, M.D., Ph.D. (Current affiliation: Harvard Medical School)

Education:

Ph.D. in Chemistry (biological chemistry division) 2008 2008

University of Utah, Salt Lake City, UT

Department of Chemistry

Thesis: Biosynthesis and regulation of heme A: an obligatory cofactor in cytochrome c oxidase

Advisor: Eric L. Hegg, Ph.D. (Current affiliation: Michigan State University)

M.S. in Chemistry (analytical chemistry division) 2001

Xiamen University, Xiamen, China

Department of Chemistry

Thesis: Photochemical fluorescence characteristics of nitrazepam and its application

Advisors: Weiping Cai and Jingou Xu

B.S. in Chemistry 1998

Yantai University, Yantai, China  

Department of Applied Chemistry


报告内容简介:

 

Abstract: BRAF is the most frequently mutated kinase in human cancers and is one of the major effectors of oncogenic RAS, making BRAF a target of considerable interest for anti-cancer drug development. Wild-type BRAF and a variety of oncogenic BRAF mutants are dependent on dimerization of the kinase domain, which also emerges as a culprit of drug resistance and side effects of current BRAF therapies. Thus, allosteric BRAF inhibitors capable of disrupting BRAF dimers could abrogate hyperactivated MAPK (mitogen-activated protein kinase) signaling driven by oncogenic BRAF or RAS and overcome the major limitations of current BRAF inhibitors. To establish this, we applied an in silico approach to design a series of peptide inhibitors targeting the dimer interface of BRAF. One resulting inhibitor was found to potently inhibit the kinase activity of BRAF homo- and heterodimers. Interesting, the biological function of BRAF is not only dependent on its catalysis activity but also the scaffolding role independent of kinase activity, supported by the occurrence of kinase-dead mutations in BRAF. We applied biochemical, biophysical, and computational approaches to investigate the role of the scaffolding function and found that the peptide inhibitor potently eliminates the scaffolding function of BRAF by disrupting BRAF dimers. As expected, the peptide inhibitor diminishes MAPK signaling driven by kinase-dead BRAF mutants, which occur frequently in lung carcinomas. Moreover, this inhibitor synergizes with FDA-approved, ATP-competitive BRAF inhibitors against dimeric BRAF, suggesting that allosteric BRAF inhibitors have great potential to extend the application of current BRAF therapies. Additionally, targeting the dimer interface of BRAF kinase leads to protein degradation of both RAF and MEK, uncovering a novel scaffolding function of RAF in protecting large MAPK complexes from protein degradation. In conclusion, we have developed a potent lead peptide inhibitor for targeting the dimer interface of BRAF in cancer cells. The dual function of this peptide inhibitor validates the strategy for developing allosteric BRAF inhibitors that specifically dissociate RAF dimers and destabilize the MAPK signaling complex.

 

报告时间:2020 年 7月22日 9:00-10:30

报告形式:腾讯会议ID:478 284 240

 


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