With the support of this CAREER Award from the Organic and Macromolecular Chemistry Program at the National Science Foundation, Professor Bogdan Olenyuk, of the Department of Chemistry at the University of Arizona, will carry out fundamental studies aimed at the development of unique, highly specific small molecule-based regulators of gene expression capable of exploiting gene-specific and tissue-specific differences in transcriptional machinery composition. The main hypothesis behind the proposed research is that the process of transcription could be effectively controlled via a disruption of key transcription factor-coactivator interactions. Prof. Olenyuk's integrated research and education program focuses on design, synthesis and study of biological properties of the new class of small molecules which serve as potent and specific inhibitors of a contact between cysteine-histidine rich domains of the coactivator proteins and transactivation domains of transcription factors. The mechanistic details of such transcriptional inhibition will be explored at the molecular level by using tools and methods of chemical genetics. The proposed projects will yield broader impacts by creating a foundation for development of the unique genomic tools for such emerging fields as genetic medicine, nanomedicine and tissue engineering. The broad, multidisciplinary research platform will foster the development of necessary research skills and scientific knowledge for students at all levels at the fast evolving interface of chemistry and biomedical fields.
Professor Olenyuk will establish an innovative approach to introduce topics in chemical biology to students from diverse backgrounds in the Tucson Public School System. Working in partnership with the University of Arizona Multicultural Affairs and Student Success (MASS) group, an educational workshop in instrumentation and methodology for the Faculty Resource Network will be launched, with the goal to improve the quality of teaching and learning at its member and affiliate institutions. As a participant in the Research Experience for Undergraduates (REU) program, Professor Olenyuk will provide a collaborative research training environment to female and underrepresented minority undergraduates with the goal of fostering their aspirations to pursue scientific careers. The combined challenges of chemical and biological problems implemented as part of the education component of this CAREER program will provide an excellent educational opportunity for trainees working at the interface of chemistry and biology.
The ability to predictably and specifically alter gene expression with synthetic protein ligands is a complex but important problem, as it creates a foundation for rational design of new tools for molecular biology and, potentially, for therapeutic development. Precise control of gene expression is critical for cellular existence, with aberrant genes often regarded as a cause in development of diseases, and hence, the goal of primary importance has been to develop methods of altering gene expression in malignant cells while leaving normal cells unaffected. With the support of this CAREER Award from the Organic and Macromolecular Chemistry Program, Professor Bogdan Olenyuk, of the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, carried out a fundamental multidisciplinary study with an aim to develop unique, highly specific small molecule-based modulators of gene expression. This study has shown that the process of transcription could be effectively modulated via a disruption of the key transcription factor-coactivator interactions with allosteric small molecule ligands. In the process, the new class of small molecules – epidithiodiketopiperazines (ETPs), have been designed, that serve as potent and specific inhibitors of a contact between cysteine-histidine rich domains of the coactivator proteins and transactivation domains of transcription factors. One such designed transcriptional antagonist, dimeric ETP (see Figure), selectively disrupts the interaction of transcription factor HIF1α with p300/CBP coactivators and down-regulates the expression of hypoxia-inducible genes. We observed an outstanding anti-tumor efficacy of thse ETPs in a fully established breast carcinoma model. Treatment with the dimeric ETP resulted in a rapid regression of tumor growth. Throughout the duration of the project the mechanistic details of transcriptional inhibition have been explored at a molecular level using tools and methods of chemical genetics. The project created a foundation for the development of the unique genomic tools capable of exploiting gene-specific and tissue-specific differences in transcriptional machinery composition. The long-term impact of this research is on such emerging technologies as genetic medicine, nanomedicine and tissue engineering. The broad research platform also fostered the development of the necessary research skills and scientific knowledge for students at all levels at the fast evolving interface of chemistry, biology and medicine.
