The major focus of Dr. Hurley’s research lab is to understand, at the molecular level, the processes involved in the recognition and binding of molecules that are directed to the active sites of enzymes. The main approaches utilized in our laboratory are X-ray crystallography, inhibitor screening, detailed enzyme kinetics and mass spectrometry.
Active Research
Aldehyde Dehydrogenases
A major focus is to correlate the structural and functional characteristics of aldehyde dehydrogenases as they impact cellular function. The goal of our project is to understand the catalytic function of this important enzyme family and how manipulation of its activity through the design of small molecule modulators of its activity can affect disease outcomes. In particular, our laboratory has become interested in the roles of aldehyde dehydrogenases from family 1A (ALDH1A; isozyme 1A1, 1A2 & 1A3) in chemoresistance in certain forms of cancer and as biomarkers for cancer stem cells, also known as cancer initiating cells. Toward this end we have pursue the discovery and development of small molecule inhibitors that demonstrate selectivity toward the different enzyme that we can use as chemical tools to probe the way these enzymes impact cancer cell survival.
Glycogen Synthesis
Our second major research direction is in collaboration with Dr. Anna Depaoli-Roach, where we are interested in the structural and functional properties of the major enzyme that controls glycogen synthesis; glycogen synthase. In particular, we are interested in how manipulation of glycogen synthase can impact the outcome of diseases associated with the over-accumulation of glycogen – so called glycogen storage diseases, such as Pompe, Cori and Lafora Disease. The goal of our collaboration is to discover and develop novel inhibitors that can block further accumulation of glycogen in cellular and mouse model systems of these diseases. To facilitate the discovery and development of the novel inhibitors our laboratory is using the structure and enzyme characteristics of glycogen synthase to inform both the medicinal chemistry and biological evaluation in cell and animal models from our collaborators.
Current Grants
T32TR004389 (MPI with M. McDowell (UND))
CTSA Post-Doctoral T32 at Indiana University
T32GM144891 (MPI with G. Arrizabalaga)
IMSD at IU School of Medicine through Inclusive Biomedical Research Training Program
Recent Publications
Skurat, AV, Segvich, DM, Contreas, CJ, Hu, YC, Hurley, TD, DePaoli-Roach, AA and Roach, PJ. (2024) Impaired malin expression and interaction with partner proteins in Lafora disease. J. Biol. Chem. 300(5):107271 doi: https://doi.org/10.1016/j.jbc.2024.107271. PMCID: PMC11063907
Takahashi, C, Chtcherbinine, M, Huddle, BC, Wilson, MW, Emmel, T, Hohlman, RM, McGonigal, S, Buckanovich, RJ, Larsen, SD, and Hurley, TD. (2024) Development of substituted benzimidazoles as inhibitors of Human Aldehyde Dehydrogenase 1A Isoenzymes. Chem Biol Interact. 2024 Feb 14, 391:110910. doi: 10.1016/j.cbi.2024.110910. PMCID: PMC11062403
Ullman JC, Mellem KT, Xi Y, Ramanan V, Merritt H, Choy R, Gujral T, Young LEA, Blake K, Tep S, Homburger JR, O'Regan A, Ganesh S, Wong P, Satterfield TF, Lin B, Situ E, Yu C, Espanol B, Sarwaikar R, Fastman N, Tzitzilonis C, Lee P, Reiton D, Morton V, Santiago P, Won W, Powers H, Cummings BB, Hoek M, Graham RR, Chandriani SJ, Bainer R, DePaoli-Roach AA, Roach PJ, Hurley TD, Sun RC, Gentry MS, Sinz C, Dick RA, Noonberg SB, Beattie DT, Morgans DJ Jr, Green EM. (2024) Small molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other Glycogen Storage Disorders. Sci Transl Med Jan 17;16(730):eadf1691. doi: 10.1126/scitranslmed.adf1691. Epub 2024 Jan 17 PMCID: PMC10962247
Fastman NM, Liu Y, Ramanan V, Merritt H, Ambing E, DePaoli-Roach AA, Roach PJ, Hurley TD, Mellem KT, Ullman JC, Green E, Morgans D Jr, Tzitzilonis C. The structural mechanism of human glycogen synthesis by the GYS1-GYG1 complex. Cell Rep. 2022 Jul 5;40(1):111041. doi: 10.1016/j.celrep.2022.111041. PubMed PMID: 35793618.
Muralikrishnan V, Fang F, Given TC, Podicheti R, Chtcherbinine M, Metcalfe TX, Sriramkumar S, O'Hagan HM, Hurley TD, Nephew KP. A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer. Cancers (Basel). 2022 Jul 15;14(14):3437. doi: 10.3390/cancers14143437. PMID: 35884498; PubMed Central PMCID: PMC9318275.
