Faculty Profile

Dr. Evripidis Gavathiotis, Ph.D.

Evripidis Gavathiotis, Ph.D.

Professor, Department of Biochemistry

Professor, Department of Medicine (Cardiology)

Areas of Research: chemical biology, structural biology, drug discovery, BCL-2 family proteins, protein-protein interactions, cell death, apoptosis, mitochondria, autophagy, oncogenes, cancer, cardiovascular disease, neurodegeneration.

Professional Interests

The Gavathiotis laboratory performs innovative and rigorous basic research to seek breakthrough discoveries and translate them to novel treatments for cancer and other diseases.
We investigate structural and mechanistic insights of BCL-2 family proteins and other key proteins in cell death and cell survival pathways such as apoptosis, mitochondrial dynamics, selective autophagy and oncogenic signaling. We harness these mechanistic insights to develop first-in-class small molecules that can be used for target identification and validation and serve as the basis for novel therapeutics.  Our work in these pathways has pioneered structural and mechanistic insights, pharmacological strategies and first-in-class small molecules targeting challenging and “undruggable” targets. We are an interdisciplinary group that has expertise in structural and chemical biology, medicinal chemistry, drug design, computational and experimental screening, biochemical and cell biology approaches and in vivo pharmacology.
Molecular Mechanisms of Cell Death and Cell Survival Signaling
  1. 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 and cell survival programs leads to variety of disease conditions and understanding the molecular mechanisms that govern these 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. We have explanded our work in mechanisms of selective autophagy, mitochondrial fusion and fission and mitochondrial permeability transition-driven necrosis. Using structural biology, biochemical, biophysical and cell biology studies, we aim to elucidate the mechanisms of protein-protein interactions and define the very determinants that modulate life and death decisions in healthy and malignant cells.
  2. Aberrant regulation of survival 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, resulting from mutations in key components of the pathway or by mutations in upstream activators of the pathway, is a highly frequent event in human cancer. 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 treatments.
Chemical Biology and Drug Discovery of Pathological Protein-Protein Interactions
  • 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 protein-protein interactions. 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, chaperone-mediated autophagy and mitochondrial dynamics that are validated in genetic models and are considered challenging or "undruggable". For example, we have identified the first-in-class small-molecule: 1)  activators of pro-apoptotic BAX and demonstrated a new paradigm for pharmacologic induction of apoptosis in cancer, 2) activators of chaperone-mediated autophagy that protect cells from oxidative stress and proteotoxicity 3)  activators of  mitofusins that promote mitochondrial fusion and restore mitochondrial motility in CMT2A neuropathy 4) allosteric BAX inhibitors that inhibit apoptosis and necrosis and protect from chemotherapy-induced cardiotoxicity 5) allosteric BRAF inhibitors that overcome resistance to FDA-approved inhibitors in melanoma and colorectal tumors 6) kinase inhibitors with rationally desinged kinetic selectivity in melanoma, colorectal, lung and leukemia cancers 7) inhibitors of RARa signaling that activate chaperone-mediated autophagy and protect from neurodegeneration.  We work towards a "chemical toolbox" of activators and inhibitors of major cell death and cell survival pathways to enable us to manipulate cell signaling and fate desicion in physiological and disease conditions and provide new research tools and future therapeutics.

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, 291: 25965-25982

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, 540: 74-79

Zhang J, Johnson JL, He J, Napolitano G, Ramadass M, Rocca C, Kiosses WB, Bucci C, Xin Q, Gavathiotis E, Cuervo AM, Cherqui S, Catz SD. Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A.  J. Biol. Chem. 2017, jbc.M116.764076

Gavathiotis E* and Zhou MM. Chemical genetics and epigenetics. Curr. Opin. Chem. Biol. 2017, 39:1-3

Garner TP, Lopez A, Reyna DE, Spitz AZ, Gavathiotis E.  Progress in targeting the BCL-2 family of proteins. Curr. Opin. Chem. Biol. 2017, 39: 133-142

Karoulia Z. Gavathiotis E. Poulikakos PI.  New perspectives for targeting RAF kinase in human cancer. Nat. Rev. Cancer 2017, Oct 6.

Reyna DE, Garner TP, Lopez A, Kopp F, Choudhary GS, Sridharan A, Narayanagari SR, Mitchell K, Dong B, Bartholdy BA, Walensky LD, Verma A, Steidl U, Gavathiotis E. Direct Activation of BAX by BTSA1 Ovecomes Apoptosis Resistance in Acute Meyloid Leukemia.  Cancer Cell 2017, 32: 490–505

Antony-Debré I, Paul A, Leite J, Mitchell K, Kim HM, Carvajal LA, Todorova TI, Huang K, Kumar A, Farahat AA, Bartholdy B, Narayanagari SR, Chen J, Ambesi-Impiombato A, Ferrando AA, Mantzaris I, Gavathiotis E, Verma A, Will B, Boykin DW, Wilson WD, Poon GM, Steidl U.  Pharmacological inhibition of the transcription factor PU.1 in leukemia. J. Clin. Invest. 2017, Oct 30 doi: 10.1172/JCI92504

Galluzzi L, Vitale I, ...Gavathiotis E, ...Kroemer G. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 Cell Death Diff. 2018

Reyna DE and Gavathiotis E. Pulling the BAX trigger for tumor cell death . Oncotarget 2018, 9: 8204-8205

Bogos A and Gavathiotis E. Current insights of BRAF inhibitors in cancer. J. Med. Chem. 2018, 61:5775-5793

Rocha GA, Franco F, Krezel A, Rumsey JM, Alberti JM, Knight WC, Biris N, Zacharioudakis E, Janetka JW, Baloh BH, Kitsis RN, Mochly-Rosen D, Townsend RR, Gavathiotis E, Dorn GW. Mfn2 agonists reverse mitochondrial defects in preclinical models of Charcot Marie Tooth disease type 2A. Science 2018, 360: 336-341.

Zhang Q, Zhang J., Gavathiotis E. ICBS2017 in Shanghai-Illuminating Life with Chemical Innovation. ACS Chem. Biol. 2018. doi: 10.1021/acschembio.8b00220. PubMed PMID: 29677443.

Giricz O, Mo Y, Dahlman KB, Cotto-Rios XM, Vardabasso C, Nguyen H, Matusow B, Bartenstein M, Polishchuk V, Johnson DB, Bhagat TD, Shellooe R, Burton E, Tsai J, Zhang C, Habets G, Greally JM, Yu Y, Kenny PA, Fields GB, Pradhan K, Stanley ER, Bernstein E, Bollag G, Gavathiotis E, West BL, Sosman JA, Verma AK. The RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma. JCI Insight. 2018, 3(14).

Reyna DE, Gavathiotis E. Liposomal parmeabilization assay to study functional interactions of BCL-2 family proteins. Methods Mol. Biol. 2018, 1877: 111-119.

Garner TP, Gavathiotis E. BCL-2 Protein Family Interaction Analysis by Nuclear Magnetic Resonance Spectroscopy. Methods Mol. Biol. 2018, 1877: 217-231.

Gavathiotis E. BCL-2 family proteins. Methods Mol. Biol. 2018, 1877: i-xi.

Ow TJ, Fulcher CD, Thomas C, O’Broin P, Lopez A, Reyna, DE, Smith RV, Sarta C, Prystowsky MB, Schlecht MF, Schiff BA, Rosenblatt G, Belbin TJ, Harris JM, Childs GC, Kawachi N, Guha C, Gavathiotis E. Optimal Targeting of BCL-family Proteins in Head and Neck Squamous Cell Carcinoma Requires Inhibition of Both BCL-xL and MCL-1. Oncotarget. 2019, 10:494-510.

Zhang J, He J, Johnson JL, Rahman F, Gavathiotis E, Cuervo AM, Catz SD. Chaperone-mediated autophagy upregulation rescues megalin expression and localization in cystinotic proximal tubule cells. Front. Endocrinol. 2019 doi: 10.3389/fendo.2019.00021

Garner TP, Amgalan D, Reyna DE, Li S, Kitsis RN, Gavathiotis E. Small Molecule Allosteric Inhibitors of BAX. Nat. Chem. Biol. 2019, 15: 1-12

Chen X, Glytsou C, Zhou H, Narang S, Reyna DE, Lopez A, Sakellaropoulos T, Gong Y, Kloetgen A, Yap YS, Wang E, Gavathiotis E, Tsirigos A, Tibes R, Aifantis I. Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment. Cancer Discov. 2019, 9:1-20


*denotes co-corresponding author

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Research Information

In the News

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

More media coverage