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Research Overview

The Zacharioudakis Lab develops small molecules that target mitochondrial adaptations regulating cell death, with the goal of overcoming drug resistance in cancer. By integrating modern chemical biology approaches with  mitochondrial biology and cancer biology we aim to uncover vulnerabilities unique to cancer cells and design therapeutics that restore apoptotic sensitivity and improve treatment outcomes.

Controlling Mitochondrial Adaptations Using Small Molecules 

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Our lab aims to discover small molecules that modulate mitochondrial adaptation pathways involved in the regulation of cell death. We are currently focused on identifying cancer cell-specific inhibitors of mitochondrial fusion, as well as chemical probes that modulate cristae remodeling. Our drug discovery strategy integrates modern chemical biology approaches, such as molecular glues and hetero-bifunctional molecules, with traditional small molecule inhibitor development. Ultimately, our goal is to develop prototype therapeutics that effectively induce cell death and advance the treatment of cancer.

Investigating Novel Molecular Mechanisms that Regulate MOMP

Mitochondrial outer membrane permeabilization (MOMP) is a critical event that initiates the intrinsic pathway of apoptosis or triggers inflammation. Through MOMP, mitochondria transmit signals that determine cell fate. To tightly regulate this process, cells have evolved several control mechanisms. Emerging evidence suggests that the propensity of mitochondria to undergo MOMP differs markedly between healthy and cancer cells, and even among different types of cancer cells. Our lab, along with previous studies, has shown that MOMP can be initiated through multiple pathways, though only a few have been thoroughly characterized. Our objective is to identify novel proteins that either directly or indirectly regulate pore formation on the outer mitochondrial membrane, and to uncover new molecular mechanisms driving MOMP.

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Overcoming Drug Resistance Through Mitochondrial Targeting

Resistance to apoptosis is a defining feature of cancer, allowing tumors to evade the effects of standard treatments. This resistance may be intrinsic or acquired over the course of therapy, frequently leading to relapse and treatment failure. Our research focuses on uncovering the molecular drivers of this resistance, with a particular emphasis on mitochondrial adaptations that alter apoptotic sensitivity. Using gene editing, proteomics, and imaging, we investigate resistance pathways in solid tumors. These insights inform the design of rational drug combinations that restore apoptotic sensitivity by targeting mitochondrial vulnerabilities—ultimately aiming to overcome therapeutic resistance and improve long-term treatment outcomes.

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Zacharioudakis Group

Purdue University

Drug Discovery Building

Room 134

720 Clinic Dr, West Lafayette

IN, 47907

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