Ass.Prof. Eduard STEFAN
Universität Innsbruck
Oncokinase Lab
Program
"Empowering the identification and validation of drug candidates targeting oncoprotein and E3"
Protein kinases are central effector molecules of signal transduction, regulated through numerous means, thus making them a primary target for drug discovery. However, analyzing their physiological and mutation-driven pathological functions within intact cells is hindered due to contextdependent molecular interactions and unique scaffolding functions of respective kinase entities. Serving as molecular switches, protein kinases spatiotemporally control vital cellular functions, and dysregulation of their activity promote diseases such as cancer. We took advantage of the high sensitivity of the Kinase Conformation (KinCon) reporter system to enable recordings of activity states of full-length and cancer-associated kinases. This allows for the precise assessment of drug-candidatetarget engagements of allosteric and competitive small molecules in living cells and high-content format (Röck et al., Sci.Adv. 2019, Mayrhofer et al., PNAS 2020, Kugler et al., eLife 2024, EU/US patents). Expanding upon this groundwork, we have recently broadened our cell-based system to involve challenging protein targets such as the tumor suppressor protein p53 and the enzyme family of E3 ligases, which are pertinent to drug discovery efforts (patents pending). With this extended target-engagement reporter platform, we are now setting out to systematically track small molecule interactions, validate drug-candidate effectiveness, and evaluate specificities directly in selected cell lines. This innovative approach opens new avenues for directly identifying p53 binders and for systematic screenings, either for novel E3 ligase entities or interacting ‘warheads’. I would be happy to discuss with you how these novel types of target engagement reporters could pave the way for the identification of new types of more effective patient-tailored bioactive small molecules.
Host: Michael FREISSMUTH
Contact for questions: Helmut KUBISTA