B.S. Johns Hopkins University (2011), Chemical Engineering
7th Year MSTP
3rd Year Medical Student
Molecular & Cellular Pharmacology
Protein kinase inhibitors are potent anti-cancer therapeutics. However, their efficacy would be improved by achieving better specificity. For example, the unusually specific kinase inhibitor imatinib decreases mortality for a specific type of leukemia by 80%, but most of the other highly potent inhibitors that have been developed can not be used clinically because of unacceptable side effects that arise from non-specific inhibition of other protein kinases. Drug specificity depends on the rates of binding and dissociation between the drug and both the target kinase and competitor kinases. Kinetic optimization of inhibitors could aid the notoriously difficult challenge of developing efficacious kinase inhibitors. For example, the slow binding drug imatinib is highly selective for Abl kinase, while the fast binding drug dasatinib is far less selective. Additionally, in the non-equilibrium environment of the cell, mutations that increase the drug release rate from its target, could cause drug resistance. Not surprisingly, the concept of drug residence time has emerged as a superior predictor of cellular drug efficacy. Understanding the process of inhibitor binding to proteins is the first step towards rational optimization of inhibitor binding kinetics. Recent structure and dynamics experiments have led to the hypothesis that the rate of drug binding to kinases and the release of drugs from kinases can be limited by the accessibility of the binding site. We have identified patient-derived resistance mutations that show no change in equilibrium affinity for imatinib and rather are “kinetically” resistant to imatinib. The results of this work are expected to provide insights into how ligands find their binding sites on proteins, leading to new strategies for improving drug specificity and efficacy by incorporating binding kinetics in the design of therapeutics. On a broader level, this study will show how the rates of conformational changes in protein kinases relate to their function and regulation.
- S Aleem, G Georghiou,RE Kleiner, K Guja, BP Craddock,A Lyczek, AI Chan, M Garcia-Diaz, T Miller,DR Liu, MA Seeliger. Structural and biochemical basis for intracellular kinase inhibition by Src-specificpeptidic macrocycles. Cell Chemical Biology. 2016; 23(9):1103-12.
- R Huculeci, E Cilia,A Lyczek, L Buts, K Houben, MA Seeliger, Nvan Nuland, T Lenaerts. Dynamically coupled residues within the SH2 domain of FYN are key to unlock its activity. Structure.2016; 24(11):1947-1959.
- A Lyczek, A Arnold, J Zhang, JT Campanelli, M Janowski, JWM Bulte, P Walczak.Transplanted Human Glial-Restricted Progenitors Can Rescue the Survival of Dysmyelinated Mice Independent ofMyelination. Experimental Neurology. 2017;291:74-86. doi: 10.1016/j.expneurol.2017.02.005.
- M Janowski,A Lyczek, C Engels, J Xu, B Lukomska, JWM Bulte, P Walczak. Cell size and velocity ofinjection are major determinants of the safety of intracarotid stem cell transplantation.J Cereb BloodFlow Metab.2013;33(6): 921-7.
- Y Liang, L Aagren,A Lyczek, P Walczak, JWM Bulte. Neural progenitor cell survival in mouse braincan be improved by co-transplantation of helper cells expressing bFGF under doxycycline control.Experimental Neurology. 2013;247:73-9.
- M Janowski, C Engels, M Gorelik,A Lyczek, S Bernard, JWM Bulte, P Walczak. Allograft survival ofglial restricted precursors within CNS is highly dependent on transplantation site in immune competentrecipients. Cell Transplantation. 2014;23(2): 253-62