Abstract 971: Chaperone-mediated protein degradation (CHAMP): A novel technology for tumor-targeted protein degradation

Abstract The HSP90 chaperone mediates folding of many important client proteins and mutated oncoproteins, but can also direct its substrates towards degradation by the ubiquitin-proteasome system. Further, in tumor tissues, HSP90 complexes are in a highly activated state relative to normal tissues, which results in HSP90-binding small molecule compounds displaying unique tumor-selective pharmacokinetics. In order to take advantage of these attributes of HSP90 to degrade the transcription factor BRD4 in a tumor-selective fashion, hetero-bifunctional small molecule compounds were synthesized, termed chaperone-mediated protein degraders (CHAMPs), that chemically induced proximity between BRD4 and HSP90. In vitro, treatment of MV-4-11 leukemia cells with a BRD4-CHAMP compound resulted in formation of a BRD4:CHAMP:HSP90 ternary complex and subsequent proteasome-dependent BRD4 degradation and inhibition of cell proliferation. CHAMPs were identified that induced selective degradation of BRD4 and displayed only minimal effects on other HSP90-regulated client proteins. While BRD4 is a known HSP90 client protein, non-HSP90 clients such as mutated KRAS could also be degraded using this approach. In vivo, in the MV-4-11 mouse xenograft model, a selective BRD4-CHAMP compound displayed prolonged pharmacokinetics in tumors relative to plasma and normal tissues, with its tumor concentration remaining above the in vitro cytotoxicity EC50 value for at least 7 days following a single dose. This resulted in greater than 90% and prolonged degradation of BRD4 in tumors, as well as decreased expression of the BRD4-regulated MYC gene. Treatment with BRD4-CHAMP at its MTD resulted in dramatic tumor regressions after a single dose and the majority of tumors were undetectable following 3 weekly doses. In contrast, daily dosing of a clinical stage pan-BET inhibitor at its MTD resulted in stable to progressive disease, indicating that BRD4-CHAMP has a greatly improved therapeutic index in this model. CHAMP technology has a number of advantages relative to other targeted protein degradation approaches, such as PROTAC, including an improved safety margin due to selective accumulation in tumor tissues. Citation Format: Kevin P. Foley, Long Ye, Mingkai Wang, Chenghao Ying, Wei Yin, Lingjie Zhang, Weiwen Ying. Chaperone-mediated protein degradation (CHAMP): A novel technology for tumor-targeted protein degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 971.