PROTACs are heterobifunctional molecules that target hard-to-drug proteins to treat diseases like cancer, diabetes, and Alzheimer’s. They consist of a targeting ligand for a disease-causing protein paired with an E3 ubiquitin ligase ligand through a flexible linker.
PROTACs typically violate one or more of Lipinski’s Rule-of-Five (Ro5) due to their high molecular weight (> 500 Da), excessive H-bond donors/acceptors (> 5/10) and elevated lipophilicity (cLogP > 5). These properties compromise their pharmacokinetic profile, particularly oral bioavailability and aqueous solubility. In addition, these compounds are typically highly potent and require specialized handling in R&D and production. PROTACs may also be challenging to isolate as crystalline solids (desirable at scale), owing to their incorporated flexible linkers.
HPAPIs and Complex Chemistry
PROTACs require facilities designed to handle HPAPIs. In addition, the inherent flexibility in the molecules due to the nature of the linker often presents challenges in purification. Chromatography is a powerful tool, offering critical purification capabilities that complement and enhance crystallization efforts.
- Veranova’s facilities are designed with SafeBridge® category 4 capabilities in Process R&D, Analytical R&D, and GMP manufacturing suites.
- We address chirality issues by optimizing the selection of warhead stereoisomers and confirming the chosen chirality through advanced analytical characterization.
- Veranova has extensive chromatography expertise and experience, performing chromatography for diverse chemistries from analytical to multi-kg production.
Improving PROTAC’s Bioavailability
The bioavailability of poorly water-soluble drugs is a significant challenge in drug development, affecting many new chemical entities. For oral dosage pharmaceutical forms, aqueous solubility is a crucial, fundamental factor for achieving bioavailability and therapeutic activity.
Our specialized, highly experienced team is adept at overcoming challenges related to the solubility and bioavailability of APIs which are common to PROTACs:
- Solid Form Screening – we modify and improve aqueous solubility through tried and tested crystal engineering strategies, specifically via salt and cocrystal screening. We utilize polymorphism studies to ensure the optimal solid form is selected. The output improvements in crystallization via solid form screening often lead to enhanced isolation and scale-up opportunities.
- Amorphous Solid Dispersions (ASD) – where crystalline materials cannot be obtained and/or have insufficient solubility/bioavailability, we employ ASD screening strategies to achieve developable solubility/dissolution behavior and improved stability compared to amorphous API itself which is often not acceptable as pure amorphous form.
- Particle Engineering – we employ a range of additional strategies to reduce particle size which effectively optimizes dissolution properties as well as use milling/crystallization processes to improve dispersibility and reduce aggregation and agglomeration of drug particles.
Optimizing PROTAC’s Crystallization
With our extensive in-house experience in crystallizing complex molecules, including PROTACs, Veranova is able to confidently tackle their common inherent challenges. We implement well-designed crystallization workflows for molecules with flexible linkers that hinder crystallization. We leverage salt and cocrystal formation strategies to investigate crystallinity often in parallel with solid form investigations to optimize aqueous solubility. We design robust crystallization protocols to enhance the developability (isolation, stability, and scalability) of lead candidates and intermediates.
Figure 1. Flowchart illustrating the development and scale-up of PROTACs.
Veranova provides a wide range of services for full lifecycle of drug development to commercial manufacturing. We can offer one or multiple services simultaneously to meet your specific requirements.
