College of Pharmacy
“The shadow proves the sunshine” – Jon Foreman
Nick Cockroft graduated Magna Cum Laude from Kalamazoo College with a B.A. in Chemistry in June 2014. During his undergraduate career, he worked in the lab of Dr. Jeffrey Bartz studying the photodissociation of nitrogen oxide-containing organic compounds and was a summer intern at Western Michigan University in Dr. Brian Young’s lab where he worked on biosensor and assay development. Nick entered Ohio State University’s Medicinal Chemistry and Pharmacognosy graduate program in July 2014 and joined the Li laboratory. In the Li lab, Nick has worked on scoring function development for molecular docking software, lead optimization and analogue development of signal transducer and activator of transcription 3 (STAT3) inhibitors, and has performed docking simulations for collaborators within the department. Nick looks forward to gaining further expertise with computational tools, improving them, and is eager to apply them to drug discovery and development.
Discovery of an Orally Available STAT3 Inhibitor (LY-17)
Using Multiple Ligand Simultaneous Docking (MLSD)
Targeting signal transducer and activator of transcription 3 (STAT3) is a potential anticancer strategy. However, STAT3 inhibitors with good selectivity and bioavailability are rare. The aim of this study was to discover selective direct STAT3 inhibitors with good drug-likeness. A new FBDD method, multiple ligand simultaneous docking (MLSD), was employed during the fragment library screening and combination process. Using MLSD, compound 9 (LY-17) was designed as an orally bioavailable STAT3 inhibitor, which presented superior druggability and selectivity to other representative STAT3 inhibitors. 9 directly and selectively inhibited the pY705 site of STAT3 with an affinity (Ki) of 440nM. The IC50 of 9 for breast cancer cell MDA-MB-231 was 184-fold lower than its IC50 for normal breast epithelial cell MCF-10A. 9 in vivo induced significant anti-tumor responses better than Gefitinib and exhibited less toxicity than Doxorubicin. This study demonstrates the potential of using the MLSD method for drug discovery.