Protein kinases act as master regulators of multiple key processes within the cell cycle, such as transcription factors, receptor regulators or enzymatic modulators. Aberrant regulation of their activity has been associated with a large number of pathological conditions, including (but not restricted to) inflammatory diseases. Therefore, protein kinases constitute promising targets for drug development, and numerous preclinical and clinical programs for kinase inhibitors are ongoing.
In this webinar, the featured speaker will examine the challenges associated with the preclinical development of kinase inhibitors. They will provide insights into the strategies used to screen new chemical entities, as well as the key steps, checkpoints and custom tools used throughout the hit-to-lead and lead optimization phases. Three kinases will be used as examples: RIPK1, RIPK2 and TYK2.
In the preclinical development of kinase inhibitors, it is important to employ a sequential process — selecting only the best compounds at each stage, with the goal of retaining only one or two optimized leads by the end of the process.
The first step consists in developing and performing in vitro assays for direct kinase inhibition testing. Active compounds can then progress to a phenotypic cell assay (such as necroptosis in the case of RIPK1) and undergo inhibitor selectivity testing (to ensure absence of inhibition of other related kinases). Lastly, interferences with blood components, such as plasma proteins, should be evaluated by performing inhibition tests in a whole blood system.Once active and selective inhibitors have been selected, drug metabolism and pharmacokinetics (DMPK) steps enable a rigorous selection of compounds with suitable absorption, distribution, metabolism and excretion profiles. Mathematical models, when provided with the in vivo and in vitro DMPK data from rodent systems, can extrapolate probable in vivo parameters in humans from in vitro assays performed on human samples, helping with future dose calculations.
Although in vivo activity should be relatively predictable using the combination of in vitro activity and PK parameters, it is still necessary to test compound activity in vivo to validate the PK/PD model. In parallel, target validation may be documented using clinically relevant disease models. For instance, TYK2 inhibitors were demonstrated to be effective in a psoriasis model, and RIPK2 inhibitors were evaluated in a colitis model. These studies resulted in the selection of a promising RIPK2 inhibitor, which has now progressed to Phase I clinical trials in early 2023.
Watch this webinar to learn about the preclinical development of kinase inhibitors for the treatment of inflammatory diseases.
Key learning objectives:
Attendees will discover:
- The significance of global preclinical development strategies in the race to launch new kinase inhibitors
- How to optimize the in vitro, DMPK, and proof-of-concept steps of a protein kinase inhibitor preclinical development program
- How to effectively test activity, specificity, assess suitable ADME properties and validate target and compounds in relevant disease models
About our speakers :
Dr. Pauline Bornert, Study & Research Director, Oncodesign Services
Dr. Pauline Bornert is a Study Director and a Scientific Referent for inflammatory, autoimmune and infectious diseases projects at Oncodesign Services. After obtaining her doctorate in veterinary medicine at the National Veterinary school of Maisons-Alfort in 2018, she completed a PhD in neuroscience at the Paris Brain institute and joined Oncodesign in 2021. In her current role, Pauline handles R&D programs for customers. She specializes in in vivo rodent and primate models of inflammatory and infectious diseases and is responsible for the PK/PD and PoC steps of preclinical projects, both in the context of integrated offers (INPACT) or isolated projects (SOLO).