The primary goal of this proposal is to adopt a multi-disciplinary approach towards the discovery and characterization of novel small molecules that target allosteric surface cavities of procaspases 3, 7 and 9 in order to elicit agonistic activity. Ideally, intracellular small molecule activators of these """"""""effector"""""""" procaspases will then promote cellular apoptosis in lieu of the normal, highly-controlled proteolytic activation by upstream """"""""initiator"""""""" caspases, or incorporation into the apoptosome. Identification and characterization of these allosteric sites and corresponding agonists with high throughput screening and fragment-trapping will further elucidate the structural rearrangements that occur upon activation in the absence of proteolytic cleavage of caspases 3 and 7. Furthermore, these results will shed light on the activation mechanism of procaspase 9 during assembly of the apoptosome complex. The ultimate goal is to identify novel mechanisms and lead compounds that promote apoptosis in tumor cells as a major first step towards caspase-directed chemotherapeutic therapies. The potential benefits to apoptosis regulation by procaspase activation will also have significant rewards in the development of novel methods to target proteins for drug discovery. ? ? ?
| Zorn, Julie A; Wolan, Dennis W; Agard, Nicholas J et al. (2012) Fibrils colocalize caspase-3 with procaspase-3 to foster maturation. J Biol Chem 287:33781-95 |
| Zorn, Julie A; Wille, Holger; Wolan, Dennis W et al. (2011) Self-assembling small molecules form nanofibrils that bind procaspase-3 to promote activation. J Am Chem Soc 133:19630-3 |
| Sadowsky, Jack D; Burlingame, Mark A; Wolan, Dennis W et al. (2011) Turning a protein kinase on or off from a single allosteric site via disulfide trapping. Proc Natl Acad Sci U S A 108:6056-61 |
| Wolan, Dennis W; Zorn, Julie A; Gray, Daniel C et al. (2009) Small-molecule activators of a proenzyme. Science 326:853-8 |
