The Moellering Laboratory of Chemical Biology is focused on the development of novel chemical tools and technology platforms to map and manipulate protein structure, function and signaling in complex biological environments. To do so, we have developed and applied an array of novel proteomic technology platforms, chemical probes and therapeutic modalities. A unifying biological theme of our research is understanding how the dynamic chemical and genetic environment of cells is sensed and converted into integrated signaling responses that control cellular homeostatic mechanisms, as well as how altered protein function and signaling is dysregulated in disease. Overall, our research interests are centered on the science of probing and perturbing the proteome in biological systems rather than one specific technology platform or disease context. In this context we are interested in understanding fundamental phenomena in proteome regulation, signaling, methods for quantitative measurement of proteome activity and topology, as well as creating new chemical probes and prototype therapeutics. We believe these concerted activities are capable of spanning basic and translational science, with the aim of making discoveries and methods available for the broader scientific community.
Dynamic Protein Reactive Metabolite-Mediated PTMs
Conserved Regulatory Signals, Disease Markers and Therapeutic Opportunities
We are interested in mapping regulatory interactions in normal and disease-associated metabolic programs. These efforts include understanding how protein-protein and protein-metabolite interactions, as well as their spatial compartmentalization in cells and tissues, shape the flow of metabolism. We are particularly interested in intrinsically reactive metabolite-mediated posttranslational modifications (rmPTMs) and their ability to serve as metabolic signals. A goal of these research projects is to identify regulatory nodes and coupled small molecule probes that can control them for intervention in diseases like cancer, diabetes, inflammation and aging.
Proximity Barcoding Chemoproteomic Platforms
We are interested in the development of novel “top-down” and “bottom-up” chemical proteomic platforms and probes to map proteome topology directly in native cellular environments. We are particularly interested in developing and integrating chemical proteomic methods to interrogate protein structure, function, and dynamic ‘social networks’ in native biological environments ranging from single-cells to live animals. Projects in these areas span chemical synthesis, proteomics, molecular imaging and computational method development.
New Synthetic Platforms to Target Transcription Factors and Other Challenging Protein Families in Disease
We have several projects focused on using new chemical proteomic technologies and synthetic strategies to develop small molecule and ‘synthetic biologic’ probes and therapeutics for challenging disease targets. Of recent interest, we are harnessing bioorthogonal chemistries and synthetic strategies to create pharmacologically stable ‘synthetic biologics’ for therapeutic targeting of ‘undruggable’ targets and signaling pathways, including the development of protein mimetics and artificial transcription factors . These projects merge bio-orthogonal synthetic strategies, structure-based and computational design and disease models to engineer new chemical probes and therapeutics.
University of Arizona
B.S.
2005
Harvard University
Ph.D.
2010
The Scripps Research Institute
Postdoctoral Fellow
2014
University of Chicago
Assistant Professor
2020
University of Chicago
Associate Professor
2023
University of Chicago
Professor
Present
Widespread, Reversible Cysteine Modification by Methylglyoxal Regulates Metabolic Enzyme Function
Coukos JS, Pillai KS, Lee CW, Liu KJ & Moellering RE. ACS Chem. Biol. 2022; Online Dec. 23.
Targeting of MYC with Modular Synthetic Transcriptional Repressors Derived from bHLH DNA-Binding Domains
Speltz TE, Qiao Z, Swenson CS, Shannguan X, Coukos JS, Lee CW, Thomas DM, Santana J, Fanning SW, Greene GL & Moellering RE. Nat. Biotechnol. 2023; 41(4): 541-51.
Methylglyoxal Forms Diverse Mercaptomethylimidazole Crosslinks with Thiol and Guanidine Pairs in Endogenous Metabolites and Proteins
Coukos JS & Moellering RE. ACS Chem. Biol.; 2021, 16(11): 2453-61.
In vivo imaging of the tumor-associated enzyme NCEH1 with a covalent PET probe.
Chang JW, Bhuiyan M, Tsai HM, Zhang HJ, Li G, Fathi S, McCutcheon DC, Leoni L, Freifelder R, Chen CT & Moellering RE. Angew. Chem. Int. Ed.; 2020, 59(35): 15161-5.
Photoproximity profiling of protein-protein interactions in cells.
McCutcheon DC, Lee G, Carlos AJ, Montgomery JE & Moellering RE. J. Am. Chem. Soc.; 2020, 142: 146-53.
Ultrasensitive, multiplexed chemoproteomic profiling with soluble activity-dependent proximity ligation.
Li G, Eckert MA, Chang JW, Montgomery JE, Chryplewicz A, Lengyel E & Moellering RE. Proc. Natl. Acad. Sci. U.S.A.; 2019, 116(43): 21493-500.
Versatile peptide macrocyclization with Diels-Alder cycloadditions.
Montgomery JE, Donnelly J, Fanning S, Speltz T, Shangguan X, Coukos J, Greene G & Moellering RE. J. Am. Chem. Soc., 2019; 141(41): 16374-81.
High throughput discovery of functional protein modifications by hotspot thermal profiling.
Huang JX, Lee G, Cavanaugh KE, Chang JW, Gardel ML & Moellering RE. Nat. Methods, 2019, 16(9):894-901.
A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signaling.
Bollong MJ#, Lee G#, Coukos JS, Yun H, Zambaldo C, Chang JW, Chin EN, Ahmad I, Chatterjee AK, Lairson LL, Schultz PG & Moellering RE. Nature, 2018; 562(7728): 600-4.
Sloan Research Fellow
2020
National Science Foundation CAREER Award
2019
American Cancer Society Research Scholar
2017
NIH Director’s New Innovator Award
2017
Mary Kay Foundation Scholar Award
2016
V Scholar Award, The V Foundation for Cancer Research
2015
CRF Young Investigator Award, The Cancer Research Foundation
2015
Dale F. Frey Award for Breakthrough Scientists, Damon Runyon Cancer Research Foundation
2014
NIH Pathway to Independence Award (National Cancer Institute)
2014
HHMI Postdoctoral Fellowship, Damon Runyon Cancer Research Foundation
2011
Centennial Predoctoral Fellowship, American Association for Cancer Research
2008
Vertex Excellent Graduate Research Award, American Chemical Society
2008
American Chemical Society / Gesellschaft Deutscher Chemiker Scholar Exchange
2007
UChicago scientists create molecules that can ‘turn off’ cancer growth in mice
Moellering Lab discover way to target ‘undruggable’ molecules involved in cancer