Abstract 400: Preclinical development of TQB3019: A potent and selective oral BTK degrader leveraging the OAPD® platform to overcome acquired resistance mutations
Authors: Jing Ren, Jinan Wang, Sheng Xu, Jin Liu, Ying Zhang, Xiaojin Wang, Baomin Liu, Wei Shi, Hongjiang Xu, Ling Yang, Wei Zhao, Xiquan Zhang
Journal: Cancer Research (2025)

Abstract Background: Bruton's tyrosine kinase (BTK) is a clinically validated target for the treatment of hematological malignancies. Small molecule inhibitors targeting BTK have been used in the clinic to manage B-cell malignancies. However, the emergence of BTK mutations, such as BTK C481S, ect., can lead to drug resistance to both covalent and non-covalent inhibitors. To address the acquired resistance mutation issues, here we report TQB3019, a novel BTK degrader, discovered using Chia Tai Tianqing's proprietary Platform for Orally Available Protein Degrader (OAPD®). Result: TQB3019, a highly potent oral BTK degrader, induced robust BTK degradation with a DC50 of less than 0.1 nM and Dmax of greater than 95% in DLBCL cell line OCI-LY10 at 6 hours. Proteomics studies revealed excellent degradation selectivity, then no Ikaros and Aiolos degradation was further confirmed in OCI-LY10 cells and human T cells. TQB3019 also exhibited efficient degradation kinetics in cells harboring both wild-type and C481S mutation, achieving 80% of BTK degradation within 2 hours at 10 nM. Importantly, TQB3019 induced strong cell proliferation inhibition in cells carrying wild-type BTK (IC50 of sub-nanomolar range) and BTK C481S mutation (IC50 of single-digit nanomolar range). TQB3019 exhibits favorable kinase selectivity of BTK over EGFR, and did not degrade EGFR in lung cancer cell line A431. Unlike covalent inhibitor ibrutinib, TQB3019 also demonstrated improved selectivity for BTK over TEC. TQB3019 using a novel designed CRBN ligand showed over 14-fold higher binding affinity to CRBN protein compared to pomalidomide. Additionally, TQB3019 showed weak inhibition of hERG and cytochrome P450 activities (CYPs) (hERG IC50 &amp;gt;30 μM and CYPs IC50 &amp;gt;10 μM). TQB3019 demonstrated promising metabolic stability in vivo with a mean residence time (MRT) of over 10 hours in dogs, and exhibited good oral bioavailability in both rodents and dogs. Furthermore, oral administration of TQB3019 led to dose-dependent tumor growth inhibition (TGI&amp;gt;95% at 15mg/kg) even complete tumor regression (30mg/kg) in a BTK wild-type TMD8 xenograft tumor model, without significant weight loss. Conclusion: Developed using Chia Tai Tianqing’s OAPD® platform, TQB3019 is an orally available BTK degrader with promising potency, superior selectivity, and favorable pharmacological properties. With IND (Investigational New Drug) application forthcoming, TQB3019 represents a promising therapeutic candidate to address resistance challenges associated with traditional BTK inhibitors. Citation Format: Jing Ren, Jinan Wang, Sheng Xu, Jin Liu, Ying Zhang, Xiaojin Wang, Baomin Liu, Wei Shi, Hongjiang Xu, Ling Yang, Wei Zhao, Xiquan Zhang. Preclinical development of TQB3019: A potent and selective oral BTK degrader leveraging the OAPD® platform to overcome acquired resistance mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 400.