5 years ago

Microfluidic-Enabled Intracellular Delivery of Membrane Impermeable Inhibitors to Study Target Engagement in Human Primary Cells

Microfluidic-Enabled Intracellular Delivery of Membrane Impermeable Inhibitors to Study Target Engagement in Human Primary Cells
Bu Wang, Michael Vazquez, Jean-Baptiste Telliez, Lee Roberts, Jonathan Brian Gilbert, Mark Bunnage, Steve W. Kortum, Atli Thorarensen, Erik Hett, Betsy S. Pierce, Brian M. Juba, Michael Pacheco, Joseph W. Strohbach, Jing Li, Armon Sharei, Lyn H. Jones
Biochemical screening is a major source of lead generation for novel targets. However, during the process of small molecule lead optimization, compounds with excellent biochemical activity may show poor cellular potency, making structure–activity relationships difficult to decipher. This may be due to low membrane permeability of the molecule, resulting in insufficient intracellular drug concentration. The Cell Squeeze platform increases permeability regardless of compound structure by mechanically disrupting the membrane, which can overcome permeability limitations and bridge the gap between biochemical and cellular studies. In this study, we show that poorly permeable Janus kinase (JAK) inhibitors are delivered into primary cells using Cell Squeeze, inhibiting up to 90% of the JAK pathway, while incubation of JAK inhibitors with or without electroporation had no significant effect. We believe this robust intracellular delivery approach could enable more effective lead optimization and deepen our understanding of target engagement by small molecules and functional probes.

Publisher URL: http://dx.doi.org/10.1021/acschembio.7b00683

DOI: 10.1021/acschembio.7b00683

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