DC 16: Signaling network modeling of the mTOR and PK-PD modeling of the drug candidates

Project part of Work Package 3

Objectives: DC16 will predict the metabolic stability and blood brain barrier penetration of compounds from existing S6K2 and PI3Kα inhibitor libraries (EKUT-Gehringer and UNIBAS-Wymann). Since most of these compounds are targeted covalent inhibitors with a certain intrinsic reactivity, DC16 will place particular emphasis on the generation of suitable models for prediction of extrahepatic clearance. The simulations and models will support strategic decision making by prioritizing compounds for further evaluation. Moreover, DC16 will pursue predictive PK/PD modeling of promising virtual hit structures from structure-based design to select synthesis candidates. DC16 will also perform toxicity prediction and prediction of BBB penetration. Since PROTAC degraders (synthesized by EKUT-Gehringer) are particularly difficult to optimize in terms of ADMET properties due to their high molecular weight and (so far) limited training data, DC16 will use the specific PD Value expertise to establish tailor-made models enabling the simulation of the in vivo properties of such compounds. Jointly with Ukessen-Thedieck, PD value has linked their PK-PD models to ODE based dynamic models of the mTOR network to predict altered mTOR network dynamics upon physiological inhibitor concentrations. DC16 will link PK-PD outputs on S6K2 and PI3Kα inhibitors to ODE mTOR network models parameterized on dynamic data from TSC1 versus TSC2 deficient cell models and patients. Hence, DC16 will simulate the physiological drug response upon TSC1/2 deficiency.

Expected Results: Derive predictive PK-PD models and simulations of metabolic stability and blood brain barrier penetration for S6K2 and PI3Kα inhibitors and link them as input to TSC1/2 specific mTOR network models. The results will support the medicinal chemistry projects of this consortium (DC13-15).

Planned secondments: 2 months at EKUT for data evaluation and initiation of PK-PD modelling of S6K2 inhibitors. 2 months at UniBas for ata evaluation and initiation of PK-PD modelling of mTOR/PI3Kα inhibitors, 2 months at ICM for modelling of the mTOR pathway based on new gene discovery.