Structure-based-drug design, energetics of drug-receptor binding, discovery of drugs for cancer and autoimmune diseases, new drug discovery methods, strategies and applications in combinatorial chemistry, drug development, medicinal and synthetic organic chemistry.
A broad-based peptide substrate directed protein kinase inhibitor discovery program was previously the focus of the lab from about 1990 and until about 2002. This project utilized computer-aided-drug design and combinatorial synthetic chemistry technologies in an iterative and complementary fashion. This research matured to the point that it was patented (US Patents 7,070,936 B1 & 7,005,445 B2) and a new biopharmaceutical company was formed based upon the technology. Compounds generated partly from the technology are progressing through clinical trials in cancer patients, and for other indications (e.g. KX2-391, US Patent 7,300,931 B2 and KX2-361, US Patent 8,003,641 B2). The discovery, preclinical, and clinical development story for KX2-391 and KX2-361 is summarized in the publication Smolinski et al Journal of Medicinal Chemistry 2018, 61, 4704-4719. The preclinical data for KX2-361 is more fully presented in the publication Ciesielski et al Journal of Neuro-Oncology 2018, 140, 519–527. As this research progressed at Kinex Pharmaceuticals it was phased out of the University at Buffalo lab. I took a half time leave of absence from my faculty position in 2010-2011 and then a full time leave of absence from my faculty position in 2012-2013 to increase my efforts as Kinex Pharmaceuticals Chief Scientific Officer (CSO). I then formally retired from my faculty position in 2013 to continue as Kinex’s CSO full time. Kinex Pharmaceuticals was later renamed Athenex, Inc. (www.athenex.com) in 2015, carried out a successful IPO on the Nasdaq stock exchange on June 14, 2017, and has grown into a successful global biopharmaceutical company. I formally retired from Athenex as the CSO in December 2016. Nevertheless our University at Buffalo fundamental research program described below continued as the publication list shows.
Molecular recognition between proteins and their ligands in an aqueous environment is a fundamental process in biology. A more complete and detailed chemical characterization of this process is needed to better understand and predict the geometry, and more particularly the strength, of ligand-protein binding. These fundamentals also extend beyond protein-ligand binding into molecular recognition in biological systems more generally. We are attempting to systematically dissect the ligand binding energetics into enthalpy, entropy, enthalpy/entropy compensation, desolvation and cooperativity components. Our approach utilizes: 1) structure-based analog design to address specific questions, 2) synthesis of the analogs, 3) characterization of the binding process with biochemical assays for the free energy of binding, isothermal calorimetry (ITC) to dissect out the enthalpy and entropy of binding, surface plasma resonance for on and off rates (Biacore), x-ray crystallography of the bound complexes to establish binding mode, and computations such as molecular dynamics to gain additional insights beyond the experimental data. More details can be obtained by reviewing the selection of our publications on this topic provided below.