(M1230-09-60) Advantage and Challenges of PROTAC Research, Development and Manufacturing

Purpose: PROTAC, driven by its innovative “event driven” compared to conventional “occupancy driven” mechanism, has been emerging as a promising next generation small molecule modality, particularly on traditionally difficult to target and even undruggable pharmacological targets. However, its unique tri-component chemical scaffold brings up various new challenges from early discovery to development, and to commercial manufacturing. This poster described the comprehensive R/D/M capability developed at PharmBlock (PB) to address these key challenges, and services we are able to provide to further leverage this innovative and dynamic technology together with our client globally.

Methods: In order to address a variety of challenges for PROTAC early discovery, development, and manufacturing, novel Computer Aided and Artificial Intelligence Drug Design (CADD and AIDD) methods were developed to facilitate novel PROACT focused building block (BB) design and optimization. Based on these novel BB inventory, novel target specific and high through screening methods were developed to improve the early discovery efficiency and successful rate. Furthermore, various process optimization methods and formulation enhancing methods including Amorphous Solid Dispersion were developed.

Results: A unique BB inventory was design and optimized including widely used Thalidomide based and unique E3 ligase ligands, commonly used linker motifs, particularly those utilizing PB’s world-leading sprio-, bridge-, bicyclic- ring series which potentially can provide better properties and oral bioavailability. A comprehensive screening platform was developed and optimized which can screening compound at 384-well format to significantly improve early discovery efficiency. A couple of successful process optimization cased were presented in which tough issues like reaction yields, purification, and solid state chemistry were solved. Lastly, ASD based formulation technology successfully help us addressing tough DMPK challenges for a few projects.

Conclusion: A comprehensive research, development and manufacturing service platform has been successful built and optimized by utilizing cutting edge technologies available and developed in house at PharmaBlock. This platform has been confidently verified by various projects covering different stages of PROTAC drug discovery and development pipeline, which can successfully and efficiently address various major challenges this highly promising modality is currently facing globally.

Amorphous Solid Dispersions by Spray Dry