Abstract 2049: Novel preclinical models for PROTAC evaluation: And beyond

Abstract

Abstract Proteolysis-targeting chimeras (PROTACs) are a novel class of small molecules that induce the degradation of target proteins. Unlike conventional inhibitors that disable target proteins by direct binding, PROTACs are event-driven, meaning that a single PROTAC molecule can induce the degradation of multiple target protein molecules. This catalytic mechanism allows PROTACs to achieve complete inhibition of target proteins at lower concentrations compared to conventional inhibitors, making them a promising therapeutic approach for previously considered "undruggable" targets.Despite their promise, the development of PROTACs faces several challenges. The large molecular weight of PROTACs can lead to poor cell permeability and bioavailability. Additionally, the lack of high-throughput, quantitative assays for evaluating PROTAC efficacy hinders structure-activity relationship (SAR) studies. The formation of the Protein-PROTAC-E3 ternary complex is crucial for PROTAC function, and reliable methods for assessing this interaction are essential for PROTAC development.In this poster, ChemPartner showcases a comprehensive suite of preclinical models for PROTAC evaluation, encompassing both in vitro and in vivo approaches. Using low-cost, high-throughput biochemical assays, we can provide valuable insights into PROTAC efficacy, facilitating SAR studies and elucidating the relationship between molecular structure and activity. Followed by in cell and in vivo function assays, we can test PROTAC PK/PD, toxicity, and efficacy. This suite of assays provides a powerful tool to speed up PROTAC development and reduce the fail rate. Citation Format: yuzhou xu, Jichuan Zhang, Ye Tian, Ziyu Chen, Amy Wang, Ting Ma, Qikuan Chen, Yinfei Yin. Novel preclinical models for PROTAC evaluation: And beyond [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2049.