Ubiquitin (Ub) signaling regulates most crucial aspects of eukaryotic cell biology including processes germane to cancer development and progression, namely, cell cycle control, DNA damage response, and myriad signal transduction pathways that regulate cell growth and differentiation. As such, the enzymes and key protein complexes involved in Ub signaling are prime targets for therapeutic cancer intervention, with numerous trials underway for Ub conjugation inhibitors and FDA-approved proteasome inhibitors used clinically for treatment of multiple myeloma and mantle cell lymphoma. Despite intense interest in the cancer biology and other scientific communities, the transient nature of pivotal...

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Ubiquitin (Ub) signaling regulates most crucial aspects of eukaryotic cell biology including processes germane to cancer development and progression, namely, cell cycle control, DNA damage response, and myriad signal transduction pathways that regulate cell growth and differentiation. As such, the enzymes and key protein complexes involved in Ub signaling are prime targets for therapeutic cancer intervention, with numerous trials underway for Ub conjugation inhibitors and FDA-approved proteasome inhibitors used clinically for treatment of multiple myeloma and mantle cell lymphoma. Despite intense interest in the cancer biology and other scientific communities, the transient nature of pivotal pathway intermediates and protein complexes involved in Ub signaling render them difficult to capture and characterize by traditional biochemical and structural approaches.

We have developed novel chemical methodologies to overcome these obstacles, which positions us to illuminate structural mechanisms of the Ub enzymatic machinery and keystone complexes involved in cell cycle regulation and DNA damage repair that have defied the efforts of even the most accomplished structural biologists. We will leverage the fundamental mechanistic insights resulting from our innovative combination of structural, biochemical/biophysical, and functional studies to identify novel inhibitors of Ub signaling by a combination of traditional and rational drug discovery in collaboration with investigators from the CPRIT-supported Center for Innovative Drug Discovery at UT Health Science Center San Antonio.

In conjunction with distinguished researchers at the NCI-designated Mays Cancer Center with expertise in DNA damage repair and cell cycle regulation, we are confident that our holistic approach to deciphering mechanisms of Ub signaling will provide an unprecedented opportunity to expand the repertoire of efficacious chemical compounds for applications in cancer prevention and treatment.

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