Chemical and Structural Biology of Cell Death and Survival Signaling

Evripidis Gavathiotis

The Gavathiotis laboratory investigates mechanisms 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 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 mechanistic insights, pharmacological strategies and first-in-class small molecules targeting challenging and “undruggable” targets. We have developed innovative approaches based on computational and biophysical methods as well as chemical strategies to enable the discovery and design of small molecules. Our studies have led to several prototype therapeutics that are undergoing development towards Investigational New Drug (IND) application for oncology and aging-associated diseases. 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

  • 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 expanded 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.
  • 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 following first-in-class small-molecules: 1) activators of pro-apoptotic BAX that 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 6) allosteric BRAF inhibitors that overcome resistance to FDA-approved inhibitors in melanoma and colorectal tumors 6) kinase inhibitors with rationally designed kinetic selectivity 7) inhibitors of RARa signaling that activate chaperone-mediated autophagy and protect from neurodegeneration 8) competitive BAX inhibitors that inhibit cell death and protect from chemotherapy-induced cytotoxicity. 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 decision in physiological and disease conditions and provide new research tools and future therapeutics.
  • Our integrative methodologies recently have identified novel targets and mechanism of action (MOA) for two FDA-approved inhibitors presenting novel pharmacological and clinical opportunities towards novel therapies. We continue to explore repurposing opportunities of clinical drugs for different mechanisms and targets and we currently focus to develop SARS-COV-2 anti-virals in response to the COVID-19 pandemic.

Selected References