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

Song Chen; Zhendong Chen; Lixue Lu; Yunpeng Zhao; Ronghui Zhou; Qiong Xie; Yongzhi Shu; Jun Lin; Xufen Yu; Yonghui Wang

doi:10.1016/j.ejmech.2023.115403

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

Eur J Med Chem. 2023 Jul 5:255:115403. doi: 10.1016/j.ejmech.2023.115403. Epub 2023 Apr 20.

Authors

Song Chen¹, Zhendong Chen², Lixue Lu¹, Yunpeng Zhao¹, Ronghui Zhou¹, Qiong Xie¹, Yongzhi Shu³, Jun Lin², Xufen Yu⁴, Yonghui Wang⁵

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
² School of Life Sciences and Health Engineering, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122, China.
³ Shanghai Meizer Pharmaceuticals Co., Ltd, 58 Yuanmei Road, Shanghai, 201109, China.
⁴ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: yuxufen@fudan.edu.cn.
⁵ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: yonghuiwang@fudan.edu.cn.

PMID: 37119666
DOI: 10.1016/j.ejmech.2023.115403

Abstract

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 T_1/2 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.

Keywords: ARQ-531; B-Cell lymphomas; BTK; Metabolic stability; PROTAC; Rigid linker.

MeSH terms

Agammaglobulinaemia Tyrosine Kinase
Humans
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Proteolysis Targeting Chimera*
Pyrimidines* / chemistry
Pyrimidines* / pharmacology
Structure-Activity Relationship

Substances

Agammaglobulinaemia Tyrosine Kinase
ARQ531
Proteolysis Targeting Chimera
Pyrimidines
Protein Kinase Inhibitors