Abstract 3111: The Sygnature CHARMD platform - combinatorial high-throughput assembly and review of molecular degraders

• Published in: Cancer research (Chicago, Ill.) Vol. 83; no. 7_Supplement; p. 3111
• Main Authors: Hjerpe, Roland, Birch, Louise, Brien, Alex, Cusin, Lola, Duffy, Lorna, Gourdet, Benoit, Lawrence, Rachel, MacFaul, Philip, Mortlock, Hannah, Neal, Hannah, Pearce, Christopher, Pitti, Erica, Robles, Gonzalo, Rodrigues, Edith, Scott, Catriona, Singh, Rajesh, Thomson, Stuart, Zhang, Yujia, Jordan, Allan
• Format: Journal Article
• Language: English
• Published: 04-04-2023
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-3111

Recent interest the ability to degrade oncogenic proteins has grown exponentially, and the advent of Protein-Targeting Chimeras (PROTACs) has allowed many previously undruggable targets to be specifically targeted. However, the successful development of these bioavailable heterobifunctional degraders relies on the identification of a combination of ligase recruiter, linker and exit vector that allow formation of a competent ternary complex and target degradation. To this end, conventional single-compound synthesis is time-consuming and poses challenges for selection of degrader components with predictive SAR and ADME properties of the assembled bifunctional compound.
Here, we demonstrate a high-throughput integrated platform for generation and assessment of bifunctional degraders, incorporating combinatorial chemistry using both commercial and bespoke linkers, cell-based activity assays, and assessment of in vitro DMPK properties (lipophilicity, metabolic stability and experimental polar surface area). Alongside this, we have in place computational methods for ternary complex modelling, linker design and PROTAC prioritisation.
Altogether, our approach facilitates rapid screening and identification of bifunctional lead compounds for challenging oncology targets with the potential to deliver significant patient benefit. Our platform approach has been exemplified through application to oncology targets of significant current interests and our results in this area will be highlighted.
Citation Format: Roland Hjerpe, Louise Birch, Alex Brien, Lola Cusin, Lorna Duffy, Benoit Gourdet, Rachel Lawrence, Philip MacFaul, Hannah Mortlock, Hannah Neal, Christopher Pearce, Erica Pitti, Gonzalo Robles, Edith Rodrigues, Catriona Scott, Rajesh Singh, Stuart Thomson, Yujia Zhang, Allan Jordan. The Sygnature CHARMD platform - combinatorial high-throughput assembly and review of molecular degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3111.