CAREER: Combinatorial Chemistry in the Classroom and Laboratory: Identification of Novel Small Molecule Ligands for Apoptotic Proteins

University Of Illinois At Urbana-Champaign, Urbana IL

Investigators

Abstract

With the support of the Organic Dynamics Program in the Chemistry Division, Professor Paul Hergenrother, of the Department of Chemistry at the University of Illinois- Urbana-Champaign, will investigate using small molecules to investigate and modulate biological systems. The overall goal of the research being the synthesis, identification, and use of small molecules that bind tightly and selectively to proteins involved in apoptosis. An approach to apoptosis is proposed in which small molecules that bind tightly to their protein target are synthesized and then used in vivo to "knock-out" the proteins in the pathway. Such molecules will be invaluable tools in the study of this exquisitely important system, and they also have potential as therapeutic agents. Initial protein targets will be the caspase family of cysteine proteases, as well as regulators of apoptosis such as Smac/DLABLO and IAP. The small molecules used for this study will be synthesized on the solid phase in a combinatorial fashion, and then screened for binding as small molecule microarrays. Use of small molecule microarrays are essential, as it will allow for both rapid evaluation of the library against multiple protein targets, and assessment of the selectivity of the synthesized compounds for one caspase versus another. The library aimed at the caspases will be a "focused" library and will be structurally biased towards compounds that will inhibit cysteine proteases. The library that will be screened against Smac/DIABLO, IAP, and other apoptotic proteins is a "primary" library in which an attempt has been made to maximize the diversity within the library. Such primary libraries that incorporate multiple chemical scaffolds have not been created on the solid phase, and the successful production of the library described herein will represent a significant advance in combinatorial synthesis. Professor Paul Hergenrother, of the Department of Chemistry at the University of Illinois- Urbana-Champaign, with the support of the Organic Dynamics Program for his CAREER award, will also develop an integrated program for teaching combinatorial chemistry in the classroom and applying combinatorial chemistry and high-throughput screening in the laboratory. The ultimate goal in the training of students is to create a group whose research is on the cutting edge of the chemistry-biology interface while developing in the student a wide variety of skills, from cell and molecular biology to organic synthesis.