Research in the Thorn-Seshold Group
Chemical biology designs can deliver stimulus-responsive and targetable inhibitors that allow ultrahigh precision and selectivity in both research and therapeutic applications. Our goal is to perform proof-of-concept demonstrations of these "smart" chemical designs.
Our major projects focus on DNA alkylators, microtubule inhibitors, and topoisomerase inhibitors. These cytotoxins inhibit crucial cell components (DNA, microtubules, topoisomerases) that perform many different tasks simultaneously (most famously during cellular reproduction, which is why these drugs occupy a critical role as powerful cancer chemotherapeutics). However the current inhibitors stop all those tasks indiscriminately, wherever they are in a cell or in the body. This makes understanding those individual tasks very difficult, and causes severe, therapeutically limiting side-effects when they are used in medicine.
By developing responsive or targetable inhibitors that can be controlled and directed with high specificity, we aim that our "smart" approaches will enable new high-precision studies in fundamental research. Because we work on chemical strategies and avoid genetic engineering, our compounds and ideas also have potential to be used clinically in the targeted treatment of diseases, especially cancer, where we aim that they can overcome the severe and therapeutically-limiting side-effects of current chemotherapeutics.
Our research follows these overarching themes:
- Developing molecular design strategies to perform high-precision targeting of small bioactive molecules: targeting them spatially to particular tissues / cells or subcellular areas, temporally by switching their activity on and off at will, and biochemically by gating their activity to enzymatic/redox processes or by directing them to specific subcellular compartments.
- Using known structures and binding site information to design novel pharmacophore scaffolds that enable new layers of functionality in biological applications.
- Using fluorescence, FRET, photoisomerisations, and photoreactivity, with our new scaffolds, to generate functionally photoresponsive reagents for chemical biology (photoactivatable, photoswitchable, fluorescent reporter, theranostic, and/or photoreactive inhibitors).
See the specific research pages for more information.