Profile image for Evripidis Gavathiotis

Evripidis Gavathiotis, Ph.D.

Area of research

  • chemical biology, structural biology, medicinal chemistry, drug discovery, BCL-2 family proteins, protein-protein interactions, kinase signaling, cell death, apoptosis, mitochondria, autophagy, cancer, aging

Email

Phone

Location

  • Albert Einstein College of Medicine Jack and Pearl Resnick Campus 1300 Morris Park Avenue Golding Building 01 Bronx, NY 10461


Research Profiles

Professional Interests

Dr. Gavathiotis is a tenured Professor in the Departments of Biochemistry, Medicine, and Oncology at Albert Einstein College of Medicine, Co-Leader of the Cancer Therapeutics Program at the Montefiore Einstein Comprehensive Cancer Center and a faculty member of the Einstein Institute for Aging Studies, the Wilf Family Cardiovascular Research Institute and the Gottesman Institute for Stem Cell Research and Regenerative Medicine.

With over twenty years of experience in chemical and structural biology, medicinal chemistry, and molecular pharmacology, Dr. Gavathiotis has built an internationally recognized research program that bridges basic mechanistic discovery and translational drug development.

Dr. Gavathiotis’ research focuses on deciphering how deregulated cell death and survival pathways drive cancer and age-related diseases, and on developing small-molecule therapeutics that can selectively modulate these processes. His laboratory has revealed fundamental mechanisms of apoptosis regulation, including how the pro-apoptotic protein BAX is activated or inhibited, and how mitochondrial dynamics and chaperone-mediated autophagy are modulated in cancer or under stress. The group has also pioneered computational, biophysical and chemical strategies to identify allosteric and cryptic binding sites in proteins once considered undruggable and platforms to accelerate rational drug design, leading to the discovery of first-in-class chemical probes and therapeutics that redefine how cell death and survival can be modulated in disease. Dr. Gavathiotis is best known for discovering the first small molecules that directly activate BAX, a protein that triggers cell death, providing a new way to overcome cancer resistance for the treatment of blood cancers and solid tumors.

The Gavathiotis Lab’s discoveries have produced multiple first-in-class small molecules demonstrating efficacy in preclinical models of acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL), melanoma, colorectal cancer, non–small cell lung cancer (NSCLC), and pancreatic cancer, as well as in models of chemotherapy-induced cardiomyopathy, pulmonary fibrosis, Alzheimer’s and Parkinson’s diseases, retinitis pigmentosa, and age-related macular degeneration. Several of these candidate therapeutics have been licensed to biotechnology companies and are being advanced toward Investigational New Drug (IND) applications, underscoring the translational and therapeutic impact of the laboratory’s work.

Dr. Gavathiotis leads an interdisciplinary team of graduate students, postdoctoral fellows, and staff scientists trained in chemical biology, structural biology, drug design, chemical synthesis, high-throughput screening, cancer biology, and in vivo pharmacology. The lab fosters a collaborative environment committed to rigorous basic science, innovation, and translational impact.

Dr. Gavathiotis serves on the editorial boards of several journals and regularly participates in NIH study sections, international scientific review panels, and industry advisory boards. Dr. Gavathiotis has received numerous prestigious awards recognizing both his scientific excellence and achievements, including: NIH Pathway to Independence (K99/R00) Award - Sidney Kimmel Scholar Award - Pershing Square Sohn Prize for Young Investigators in Cancer Research - Sinsheimer Scholar Award - Gabrielle’s Angel Foundation Medical Research Award - Irma T. Hirschl Career Scientist Award - AHA Collaborative Science Award - NYC BioAccelerator Prize -ICBS Young Chemical Biologist Award - Julius Marmur Mentorship Award.

Molecular Mechanisms of Cell Death and Cell Survival Signaling

Programmed cell death is essential for maintaining tissue homeostasis and proper development in multicellular organisms. Its deregulation contributes to a wide range of diseases, particularly cancer. Our laboratory focuses primarily on BCL-2 family proteins and their role in mitochondrial apoptosis, while also exploring the molecular regulation of mitochondrial fusion and fission, selective autophagy, RAS/MAPK signaling, and cellular senescence. By integrating chemical biology, structural biology, biochemistry, and cell biology, we aim to elucidate the fundamental mechanisms that that govern life-and-death decisions in cells and to translate these insights into novel therapeutic opportunities.

A list of key contributions of molecular mechanisms and insights from our laboratory include:

  • Discovery of the BAX trigger site and its role in the mechanism of BAX activation, translocation, and oligomerization during apoptosis (Nature 2008, Mol Cell 2010, Nat Chem Biol 2012, JBC 2015, Mol Cell 2016, Nat. Commun 2021, Nat. Commun 2023)
  • Structure of the autoinhibited BAX dimer and its mechanism of regulating apoptosis (Mol Cell 2016, Nat. Commun 2023)
  • Elucidation of BRAF allosteric activation mechanisms by inhibitors and structural basis of RAF inhibitors activity (Cancer Cell 2016)
  • Structural mechanisms of Mitofusins activation/inhibition regulating mitochondrial dynamics (Nature 2016)
  • Allosteric mechanism of BAX inhibition and discovery of novel allosteric site regulating BAX conformational activationand apoptosis (Nat Chem Biol 2019, Nature Cancer 2020)
  • Allosteric mechanism of BRAF dimerization control and discovery of BRAF allosteric site (Nature Communications 2020, eLife 2025).
  • Mechanistic insights into BAX inhibition and conformational control (Moll Cell 2016, Nat Commun 2021)
  • Mechanisms of small molecule BAX activation in cancer cells and apoptosis regulation by BCL-XL and BCL-2 (Cancer Cell 2017, Nat Commun 2022, Nat Commun 2023)
  • Link between mitochondrial fusion inhibition to mitochondrial outer membrane permeabilization, caspase-3/7 activation and DNA damage (Nat Commun 2022)
  • Selective Chaperone-mediated Autophagy (CMA) activation via RARα/NCoR1 interaction stabilization (Nat Commun 2022)
  • Mechanism of BH3 mimetic resistance in AML through increased mitofusin-2 activity and mitophagy (Cancer Discovery 2023)
  • Mechanism of apoptosis resistance via cytosolic BAX dimerization (Nat Commun 2023)
  • Mitofusin-mediated regulation of nucleic acid release and SASP (Nat Commun 2024)
  • CMA inhibition through disruption of NCoR1/RARα interaction in cancer (EMBO Mol Med 2025)
Chemical Biology and Drug Discovery of Cell Death Mechanisms

We apply structure-based drug design, high-throughput screening, and medicinal chemistry to discover and optimize small molecules and peptide-based probes targeting protein–protein interactions and other challenging targets. Our objective is to generate a "chemical toolbox" of activators and inhibitors of major cell death and cell survival pathways to enable us to manipulate cell signaling and fate decision in physiological and disease conditions. These new research tools can be used to understand biological mechanisms and as prototypes for the development of novel therapeutics. Our protein targets span mitochondrial apoptosis, mitochondrial dynamics, autophagy, and oncogenic kinase signaling, many of which are traditionally considered "undruggable".

Select first-in-class small molecules from our laboratory include:

  • BAX activators inducing apoptosis in cancer (Nat Chem Biol 2012, Cancer Cell 2017, Nat Commun 2022)
  • CMA activators via RARα signaling that protect from oxidative stress and proteotoxicity (Nat Chem Biol 2013)
  • Mitofusin activators promoting mitochondrial fusion and mitochondrial function and restore mitochondrial motility in CMT2A neuropathy (Science 2018, Nat Commun 2022)
  • Allosteric BAX inhibitors protecting from apoptosis, cardiotoxicity, senescence, and neurodegeneration (Nat Chem Biol 2019, Nat Cancer 2020, Nature 2023, Neuron 2024)
  • BRAF dimer-selective inhibitors overcoming drug-resistance in melanoma and colorectal cancer (Nat Commun 2020, eLife 2025)
  • Competitive BAX inhibitors protecting from apoptosis and chemotherapy-induced cytotoxicity (Nat Commun 2021)
  • Mitofusin inhibitors inducing mitochondrial fission, mitochondrial-outer membrane permeabilization and sensitizing BH3 mimetics and SMAC mimetics to apoptosis (Nat Commun 2022, Cancer Discovery 2023) and inhibiting mitochondrial mediated senescence-associated secretory phenotype (SASP) (Nat Commun 2024)
  • RARα/NCoR1 stabilizers (molecular glues) activating CMA, protecting from neurodegeneration in Alzheimer’s models (Cell 2021), retinal degeneration (Nat Commun 2022), age-related macular degeneration (EMBO Mol. Med 2025), reversing stem cell aging (Nature 2021) and improve T-cell function (PNAS 2024),
  • BAX dimer activators that activate cytosolic BAX dimers and induce BAX-mediated apoptosis (Nat Commun 2023)
  • CMA inhibitors that suppress tumor growth via NCoR1/RARα disruption (EMBO Mol Med 2025)
  • Repurposing of ponatinib and eltrombopag based on new mechanisms (Nat Commun 2020, 2021)
  • High residence RAF kinase inhibitors with favorable pharmacological profile for targeted cancer therapy

Platform Technologies: To accelerate drug discovery, the Gavathiotis lab has developed integrative platform technologies that include:

  • High throughput in silico screening pipelines for hit discovery and prioritization
  • Allosteric/cryptic site discovery using structure- and dynamics-based prediction
  • SAR-guided lead optimization using biophysical, structural, and cellular readouts
  • Optimization of high residence time and kinetic selectivity for kinase-targeted inhibitors
  • Allosteric kinase drug discovery through structure-guided allosteric site targeting, high-throughput medicinal chemistry, and direct-to-biology screening

These platforms support scalable and rational drug discovery efforts across a broad range of targets.

Selected Publications