Discovery of novel BTK PROTACs with improved metabolic stability via linker rigidification strategy

• Published in: European journal of medicinal chemistry Vol. 255; p. 115403
• Main Authors: Chen, Song, Chen, Zhendong, Lu, Lixue, Zhao, Yunpeng, Zhou, Ronghui, Xie, Qiong, Shu, Yongzhi, Lin, Jun, Yu, Xufen, Wang, Yonghui
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.07.2023; Elsevier
• Subjects: Agammaglobulinaemia Tyrosine Kinase; ARQ-531; B-Cell lymphomas; BTK; Chemistry, Medicinal; Humans; Life Sciences & Biomedicine; Metabolic stability; Pharmacology & Pharmacy; PROTAC; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proteolysis Targeting Chimera; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rigid linker; Science & Technology; Structure-Activity Relationship; BTK; Rigid linker; Metabolic stability; B-Cell lymphomas; ARQ-531; PROTAC; TARGET; BRUTONS TYROSINE KINASE; DEGRADATION; MECHANISMS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115403

Bruton's Tyrosine Kinase (BTK) functions as a key regulator of B-cell receptor (BCR) signaling pathway, which is frequently hyperactivated in a variety of lymphoma cancers. Using Proteolysis Targeting Chimera (PROTAC) technology, we have recently discovered a highly potent ARQ-531-derived BTK PROTAC 6e, inducing effective degradation of both wild type (WT) and C481S mutant BTK proteins. However, the poor metabolic stability of PROTAC 6e have limited its further in vivo studies. Herein, we present our structure-activity relationship (SAR) studies on modifying PROTAC 6e using linker rigidification strategy to identify a novel cereblon (CRBN)-recruiting compound 3e that induced BTK degradation in a concentration-dependent manner but had no effect on reducing the level of CRBN neo-substrates. Moreover, compound 3e suppressed the cell growth more potently than the small molecule inhibitors ibrutinib and ARQ-531 in several cells. Furthermore, compound 3e with the rigid linker displayed a significantly improved metabolic stability profile with the T1/2 increased to more than 145 min. Overall, we discovered a highly potent and selective BTK PROTAC lead compound 3e, which could be further optimized as potential BTK degradation therapy for BTK-associated human cancers and diseases. [Display omitted] •Based on our previous BTK PROTAC, a novel series of BTK PROTACs with rigid linkers were designed, synthesized and evaluated.•Compound 3e (DC50 = 7.0 ± 1.4 nM, Dmax = 96%) induces BTK degradation via concentration- and UPS-dependent manners.•3e effectively inhibits the proliferation of BTK wild-type and C481S mutated cells.•3e significantly improves metabolic stability (T1/2 > 145 mins) and is metabolic stable in mouse PK studies.