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Faculty Profile

Evripidis Gavathiotis, Ph.D.

Dr. Evripidis Gavathiotis

Assistant Professor, Department of Biochemistry

Assistant Professor, Department of Medicine (Cardiology)

 

Professional Interests

The Gavathiotis laboratory focuses on chemical and structural biology to elucidate and target protein interaction mechanisms of deregulated signaling pathways in cancer and other diseases. Our goal is to translate our mechanistic and structural insights of protein interactions into novel pharmacological strategies and chemical probes that can be used for target validation and serve as the basis for novel therapeutics. Our research approach is interdisciplinary, at the interface of chemistry and biology, combining chemical synthesis, structure-based design, structural biology (NMR and X-ray crystallography), biochemistry, cellular and in vivo pharmacology.


Structural Biology of Cell Death Mechanisms
Programmed cell death is a genetically controlled physiological process that rids the body of unwanted or malfunctioning cells to maintain the normal development and homeostasis of multicellular organisms. Dysregulation of cell death programs leads to variety of disease conditions and understanding the molecular mechanisms that govern cell death signaling pathways is both fundamentally important and medically relevant. Our focus is the mitochondrial apoptotic signaling pathway and specifically the protein interaction network of the BCL-2 family of proteins. We have published the first structural analysis of a BH3 death domain in complex with pro-apoptotic BAX, uncovering a new regulatory site on BAX and providing the first glimpse into the trigger mechanism for pro-apoptotic BAX activation. We also revealed the essential role of key structural regions that undergo conformational changes upon BAX activation and enable auto-activation of BAX by a “hit and run” mechanism. Our current work, using primarily NMR spectroscopy combined with biochemical, biophysical and cell biology studies, aims to elucidate the mechanisms of protein-protein interactions and post-translational modifications to define the very determinants that modulate life and death decisions in healthy and cancer cells.
 
Chemical Biology of Cell Death and Chaperone-Mediated Autophagy Regulation
We apply high-throughput screening, structure-based drug design and medicinal chemistry to discover chemical compounds that bind to proteins and modulate their function. We will use these compounds as chemical probes to dissect signaling pathways and as templates for the development of novel therapeutics. Our targets include proteins of the mitochondrial cell death pathway and chaperone-mediated autophagy that are highly validated in in vivo models but are considered challenging or "undruggable. Recently, using structure-based drug design we identified: 1) the first small-molecule activator of pro-apoptotic BAX and demonstrated a new paradigm for pharmacologic induction of apoptosis and ii) the first class of small molecules that activate chaperone-mediated autophagy and protect cells from oxidative stress and proteotoxicity. Using drug design and medicinal chemistry for lead optimization we are currently developing these compounds as prototype therapeutics.

Structural and Chemical Biology of the MAPK/ERK Signaling Pathway
Aberrant regulation of cellular signaling pathways can lead to uncontrolled cell growth and proliferation leading to malignant transformation and tumorigenesis. Constitutive activation of the mitogen activated protein kinase (MAPK) signaling pathway is a highly frequent event in human cancer, which results from mutations in key components of the pathway or by mutations in upstream activators of the pathway. We are using chemical and structural approaches to elucidate and target novel mechanisms that regulate critical components of the MAPK signaling pathway e.g. RAS, RAF, MEK and ERK proteins. Our goals are to advance our understanding of the structure-function relationships regulating important components of the MAPK signaling pathway and provide new avenues for drug development overcoming resistance mechanisms to current therapies.
 

Selected Publications

 
 

Whelan RS, Konstantinidis K, Wei AC, Chen Y, Reyna DE, Jha S, Yang Y, Calvert JW, Lindsten T, Thompson CB, Crow MT, Gavathiotis E, Dorn GW 2nd, O'Rourke B, Kitsis RN. Bax regulates primary necrosis through mitochondrial dynamics. Proc Natl Acad Sci U S A. 2012, 109:6566-6571.

LaBelle JL, Katz SK, Bird GH, Gavathiotis E, Stewart ML, Lawrence C, Fisher JK, Godes M, Pitter K, Kung AL, Walensky LD. A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J. Clin. Invest. 2012, 122:2018-2031.

Gavathiotis E*, Reyna DE, Bellairs JA, Leshchiner ES, Walensky LD*. Direct and selective small-molecule activation of proapoptotic BAX. Nature Chem. Bio. 2012, 8:639-645.

Cohen NA, Stewart ML, Gavathiotis E, Tepper JL, Opferman JT, Walensky LD. A competitive stapled peptide screen identified a selective small molecule that overcomes MCL-1 dependent leukemia cell survival. Chem & Biol. 2012, 19: 1175-1186.

 
 
 
 
 

 

 

More Information About Dr. Evripidis Gavathiotis

Gavathiotis Laboratory website

Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.

Contact

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Golding Building, Room G01D
Bronx, NY 10461

Tel: 718.430.3725
evripidis.gavathiotis@einstein.yu.edu

 
Pubmed Search
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