Division of Cardiology

Dr. Evripidis Gavathiotis, Ph.D.

Evripidis Gavathiotis, Ph.D.

Associate Professor, Department of Biochemistry

Associate Professor, Department of Medicine (Cardiology)

Areas of Research: chemical biology, structural biology, medicinal chemistry, drug discovery, protein-protein interactions, structure-function, cell death, mitochondria, autophagy, oncogenes, cancer, cardiovascular disease

Professional Interests

The Gavathiotis laboratory aims to investigate and target mechanisms of protein-protein interactions in cell death and cell survival signaling, which are deregulated in cancer and other diseases. In this effort, we develop novel pharmacological strategies and chemical probes that can be used for target validation and serve as the basis for novel therapeutics. By operating at the interface of chemistry and biology, and developing innovative approaches, our goal is to advance our understanding of biological processes and provide new opportunities for drug discovery and development. To achieve our goal, we take an interdisciplinary approach using chemical synthesis, structure-based design, structural biology (NMR and X-ray crystallography), biochemistry, cellular and in vivo pharmacology.

Molecular Mechanisms of BCL-2 Family Proteins in Cell Death Regulation
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. Deregulation 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 protein interaction network of the BCL-2 family of proteins and its role in regulating apoptosis, necrosis and mitochondrial dynamics. Our current work, using structural biology, 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 malignant cells.
Chemical Biology of Cell Death and Chaperone-Mediated Autophagy
We apply high-throughput screening, structure-based drug design and medicinal chemistry to discover and develop small molecules and peptide-based probes that modulate the function of proteins. We use these probes to interrogate the signaling pathways and understand the biological mechanisms. Probes are also used as templates for the development of novel therapeutics. Our targets include but are not limited to proteins of the mitochondrial cell death pathway and chaperone-mediated autophagy that are highly validated in in vivo models and are considered challenging or "undruggable". For example, 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.

Molecular Mechanisms and Targeting 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

Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD. BAX Activation is Initiated at a Novel Interaction Site. Nature 2008, 455:1076-1081.
Bird GH, Madani N, Perry AF, Princiotto AM, Supko JG, He X, Gavathiotis E, Sodroski JG, Walensky LD. Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic. Proc. Natl. Acad. Sci. USA 2010, 107:14093-14098.
Braun CR, Mintseris J, Gavathiotis E, Bird G, Gygi SP, Walensky LD. Photoreactive Stapled BH3 Peptides to Dissect the BCL-2 Family Interactome. Chem. Biol. 2010, 17:1325-1333.

Gavathiotis E, Reyna DR, Davis ML, Bird GH, Walensky LD. BH3-Triggered Structural Re-organization Drives the Activation of Pro-apoptotic BAX Mol. Cell 2010, 40:481-492.

Gavathiotis E. and Walensky LD. Tracking BAX once the Trigger is Pulled. Cell Cycle 2011, 10:868-870.

Walensky LD. and Gavathiotis E*. BAX Unleashed: The Biochemical Transformation of an Inactive Cytosolic Monomer into a Toxic Mitochondrial Pore. Trends Biochem. Sci. 2011, 36:642:652

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.

Anguiano J. Garner T, Mahalingam M, Das BS, Gavathiotis E* and Cuervo AM. Chemical modulation of chaperone-mediated autophagy by novel retinoic acid derivatives. Nat. Chem. Biol. 2013, 374-382.
Edwards EL, Gavathiotis E, LaBelle J, Braun GH, Opoku-Nsiah K, Bird GH, Walensky LD. Multimodal activation of apoptosis by a hydrocarbon stapled PUMA BH3 helix. Chem. & Biol. 2013; 20: 888-902.
Gavathiotis E. Structural Perspectives on BCL-2 Family of Proteins. Cell Death - Mechanism and Disease. 2013 229-251.

Bird GH, Gavathiotis E, Labelle JL, Katz SG, Walensky LD. Distinct BimBH3 (BimSAHB) Stapled Peptides for Structural and Cellular Studies. ACS Chem. Biol. 2014, 9: 831-837.
Papadopoulos E, Jenni S, Kabha E, Takrouri KJ, Yi T, Salvi N, Luna RE, Gavathiotis E, Mahalingam P, Arthanari H, Rodriguez-Mias R, Freedman RY, Aktas BA, Chorev M, Halperin JA, Wagner G. Structure of the translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G, Proc. Natl. Acad. Sci. USA 2014, 111: E3187-E3195.
Cheng C, Liu Y, Balasis ME, Garner TP, Li J, Simmons NL, Berndt N, Song H, Pan L, Qin Y, Nicolaou KC, Gavathiotis E, Sebti SM. Marinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Bim. Mar. Drugs 2014, 12: 4311-4325.

Li R, Cheng C, Balasis ME, Liu Y, Garner TP, Daniel KG, Li J, Qin Y, Gavathiotis E*, Sebti SM. Design, synthesis and evaluation of Marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors.Eur. J. Med. Chem. 2015, 90: 315-331

Barclay LA, Wales TE, Garner TP, Wachter F, Lee S, Guerra R, Stewart ML, Braun CR, Bird GH, Gavathiotis E, Engen JR, Walensky LD. Inhibition of Pro-apoptotic BAX by a noncanonical interaction mechanism. Mol. Cell 2015, 57: 1-14. 

Chen HC, Kanai M, Inoue-Yamauchi A, Tu HC, Huang Y, Ren D, Kim H, Takeda S, Reyna DE, Chan PM, Ganesan YT, Liao CP, Gavathiotis E, Hsieh JJ, Cheng EH. An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol. 2015, 17: 1270-1281.

Uchime O, Dai Z, Biris N, Lee D, Sidhu SS, Li S, Lai JR, Gavathiotis E. Synthetic Antibodies Inhibit Bcl-2-associated X Protein (BAX) through Blockade of the N-terminal Activation Site. J. Biol. Chem. 2015, 291: 89-102.

Klionsky DJ, ..., Gavathiotis E, ...Zughaier SM. Guidelines for the use and intepretation of assays for monitoring autophagy. Autophagy. 2016, 12: 1-222.

Cotto-Rios XM, Gavathiotis E. Unraveling cell death mysteries. Nat. Chem. Biol. 2016 12: 470-471

Garner TP, Reyna DE, Priyadarshi A, Chen HC, Li S, Ganesan, YT, Malashkevich VN, Almo SS, Cheng EH, Gavathiotis E. An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway. Mol. Cell 2016, 63: 485-497.

Karoulia Z, Wu Y, Ahmed AA, Xin Q, Bollard J, Krepler C, Wu X, Zhang C, Bollag G, Herlyn M, Fagin JA, Lujambio A, Gavathiotis E*, Poulikakos P. An Integrated Model of RAF inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling. Cancer Cell 2016, 30: 1-14.

Reyna DE and Gavathiotis E. Self-regulation of BAX-induced cell death. Oncotarget 2016

Johnson JL, Ramadass M, He J, Brown SJ, Zhang J, Abgaryan L, Biris N, Gavathiotis E, Rosen H, Catz SD. Identification of Nexinhibs, small-molecule inhibitors of neutrophil exocytosis and inflammation. Druggability of the small GTPase Rab27a. J. Biol. Chem. 2016 jbc.M116.741884

Franco A, Kitsis RN, Fleischer JA, Gavathiotis E, Kornfeld OS, Gong G, Biris N, Benz A, Qvit N, Donnelly SK, Chen Y, Mennerick S, Hodgson L, Mochly-Rosen D, Dorn GW 2nd. Correcting mitochondrial fusion by minipulating mitofusin conformations. Nature 2016  doi: 10.1038/nature20156

*denotes co-corresponding author

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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
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Forchheimer Building, Room G46
Bronx, NY 10461

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Media Coverage

The Scientist interviews Drs. Nir Barzilai and Evris Gavathiotis about their success in pursuing private funding in the face of federal funding cuts.

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