Abstract 6042: CBP-8008: A first-in-class targeted pan-Bet protein degradation therapy using bi-specific XDC (Bi-XDC) technology for TNBC and mCRPC

Abstract

Abstract Bi-XDC is a breakthrough cellular targeting technology using multi-targeting ligands to effectively deliver the payload to and into specific cells. Several anticancer Bi-ligand drug conjugates including CBP-1008, CBP-1018, and CBP-1019 have been brought into various clinical stages in China and US. Targeted protein degradation molecules can degrade previously “undruggable” target proteins through their catalytic mechanism of action. The field target protein degradation has evolved since 2001, and more than 20 PROTACs are under clinical trials at different stages. To increase the efficacy vs. tolerability window, we combine Bi-XDC technology and the catalytic approach of targeted protein degradation, to form C-PROTAC, by taking advantage of our privileged Bi-XDC technology and PROTAC’s degradation property. Further medicinal chemistry optimization, spacer optimization, and evaluation of many linker payloads led to the identification of our preclinical candidate CBP-8008, a highly potent pan-Bet protein degrader conjugated to bi-ligand via a cleavable linker. A small panel of cell lines was screened to identify which tumors were sensitive to the pan-Bet protein degradation. All the tested breast cancer and prostate cell lines were the most sensitive to the payload. CBP-8008 had a high affinity to the Prostate Specific Membrane Antigen (PSMA) and the folate receptor alpha (FRα). Much more CBP-8008 were binding the 293T-FP which overexpress both FR-α and PSMA than the cell lines which only express one target (293T-F or 293T-P) or negative cell line (293T). CBP-8008 can quickly enter cells through endocytosis after treatment for 15 min, and degradation of BRD2, BRD3, and BRD4 was observed in MDA-MB-231 after 6 h, which was similar to its payload. The compound was very stable in mouse and human plasma in vitro, and limited free payload was detected which potentially avoids hematotoxicity in clinical. In the tumor-beaning mice DMPK study, fewer free payload was detected in 6 hours while much more free payload was detected in the tumor than in the blood and the time was extended to 72 hours after a single dose treatment. We evaluated CBP-8008 in TNBC and mCRPC xenograft model and robust efficacy was observed as lower as 3 MPK, significantly better than BMS-986158, a potent Bet inhibitor in clinical. In conclusion: CBP-8008 is currently in preclinical development as a potential first-in-class pan-Bet protein degradation therapy using Bi-XDC technology for TNBC and mCRPC Citation Format: Tao Wang, Zhiguang Zhang, Guitao Wang, Fan Pan, Robert Huang. CBP-8008: A first-in-class targeted pan-Bet protein degradation therapy using bi-specific XDC (Bi-XDC) technology for TNBC and mCRPC [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 6042.