Logo of Chmielewski Lab

Molecular Targets For Cancer & Aging Therapeutics: Research Overview

The overall goal of my research program is to understand the mechanisms and roles of important eukaryotic integral membrane proteins that are fundamental to human health and disease. My multidisciplinary work successfully integrates the tools of biochemistry, molecular biology, cell biology and biophysical chemistry to define how these membrane proteins recognize their substrates and how they operate at the molecular level. We also develop ways to use our mechanistic knowledge to create pharmacological agents to modulate the activities of these important proteins. Specifically, I focus on three major areas: (1) the membrane-associated enzymes involved in the post-translational processing, (2) the human ATP binding cassette (ABC) transporters ABCG2 and P-glycoprotein, and (3) drug discovery for inhibitors of human Icmt and for human ABC transporters at the blood-brain barrier.

"Christine Hrycyna leads the Department of Chemistry upward and outward"

Congrats to Prof. Hrycyna on being named a 150th Anniversary Professor!

Recent Publications

Di Micco, A., Frera, G., Lugrin, J., Jamilloux, Y., Hsu, E-T., Tardivel. A., De Gassart, A., Zaffalon, L., Bujisic, B., Siegert, S., Quadroni, M., Broz, P., Henry, T., Hrycyna, C.A., and Martinon, F., AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity, Proc Natl Acad Sci USA., 113(32):E4671-4680, 2016.

Butler, K.V., Bohn, K., Hrycyna, C.A., and Jin, J., Non-Substrate Based, Small Molecule Inhibitors of the Human Isoprenylcysteine Carboxyl Methyltransferase, Medchemcomm, 7(5):1016-1021, 2016.

Bohn, K., Lange, A., Chmielewski, J., and Hrycyna, C.A., Dual Modulation of Human P-Glycoprotein and ABCG2 with Prodrug Dimers of the Atypical Antipsychotic Agent Paliperidone in a Model of the Blood-Brain Barrier, Mol Pharm., 14(4):1107-1119, 2017.

Namanja-Magliano, H.A., Bohn, K., Agrawal, N., Willoughby, M.E., Hrycyna, C.A., and Chmielewski, J., Dual inhibitors of the human blood-brain barrier drug efflux transporters P-glycoprotein and ABCG2 based on the antiviral azidothymidine, Bioorg Med Chem., S0968-0896(17):31353-1356, 2017.

Diaz-Rodriguez, V., Hsu, E., Ganusova, E., Werst, E.R., Becker, J.M., Hrycyna, C.A., and Distefano, M.D., a‐Factor Analogues Containing Alkyne- and Azide-Functionalized Isoprenoids Are Efficiently Enzymatically Processed and Retain Wild- Type Bioactivity. Bioconjugate Chem., 29(2):316-323, 2018.

Spear, E.D., Hsu, E., Nie, L., Carpenter, E.P., Hrycyna, C.A., and Michaelis, S., ZMPSTE24 missense mutations that cause progeroid diseases decrease prelamin A cleavage activity and/or protein stability, Dis Model Mech., 11(7):1-12, 2018.

Wang, C., Zhang, B., Ratliff, A.C., Arrington, J., Chen, J., Xiong, Y., Yue, F., Nie, Y., Hu, K., Jin, W., Tao, W.A., Hrycyna, C.A., Sun, X., and Kuang, S., Methyltransferase-like 21e inhibits 26S proteasome activity to facilitate hypertrophy of type IIb myofibers. FASEB J., 33, 1-13, 2019.

Agrawal, N., Rowe, J., Lan, J., Yu, Q., Hrycyna, C.A., and Chmielewski, J., Potential Tools for Eradicating HIV Reservoirs in the Brain: Development of Trojan Horse Prodrugs for the Inhibition of P‐Glycoprotein with Anti-HIV‐1 Activity, J. Med. Chem., 63, 2131-2138, 2020.