PROTACs are among the “larger” small molecules and offer high-level selectivity for undruggable target proteins by harnessing a natural ubiquitinate system. One of the interesting things about PROTACs is that they don’t follow the rule of 5 which predicts poor absorption or permeation. The major druggability issues associated with the PROTAC compounds are low solubility, low permeability, high LogD values, high binding to plasma proteins, unusual cleavage of linkers via CYP mediated metabolism, and direct cleavage by hydrolytic enzymes. Routine in-Vitro ADME studies does not help in funnelling the PROTACS to build QSAR. Critical revisit and optimizing in-Vitro ADME assays are a must for meaningful SAR, as well as the appropriate usage of orphan excipients to evaluate the pharmacokinetic properties and move the molecules forward.
To address the ADME and PK issues associated with PROTAC molecules, the Syngene DMPK group has developed modified Caco-2 conditions and bio-relevant thermodynamic solubility assessments to select compounds for oral PK studies. The webinar will cover how we developed modified UC-PPB methods that distinguish compounds that are tightly bound and highly tightly bound to plasma proteins or tissue proteins, and thus help establish unbound plasma and tissue concentrations from PK studies. We will also discuss the identification of metabolism or degradant pathways that are associated with linkers which help in understanding and predicting the metabolism of linkers employed in the PROTACS programs.
In this webinar, we will also go over case studies that are more relevant to PROTAC molecules and discuss the utility of in-vitro ADME assays and PK studies in advancing molecules from early discovery to optimized leads.
There is no prior art available on PROTACS programs covering how to establish PK properties - many of the compounds we work with were taken directly into PK studies! (We then built the SAR using appropriate in-vitro systems to establish an IVIVE mechanism for the PROTACS.) With this webinar, we hope to share some of the key learning from the PROTACs programs we have run.
Join our webinar to gain insights into a practical strategy to delineate druggability issues associated with PROTAC programs, and to understand more about custom based ADME assays and PK studies that drive the SAR in PROTACs research.
Key Learning Objectives
- DMPK Profiling of PROTACs in Drug Discovery
- Oral formulation development for low soluble compounds
- Metabolite Identification
- PROTACs: A Powerful New Therapeutic Modality
Audience
- Head of Drug Discovery
- Head of Chemistry
- Research Director
- Head of Biology
- Chief Scientific Officer
- Head of R&D
- Head of Bioinformatics
- Head of Toxicology
- Head of DMPK
- Head of Translational Medicine
