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.ĪRQ-531 B-Cell lymphomas BTK Metabolic stability PROTAC Rigid linker.Ĭopyright © 2023 Elsevier Masson SAS. 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. ARQ-531 is a potent and orally active BTK inhibitor with potential antineoplastic activity, with IC50s of 0.85 nM and 0.39 nM for WT-BTK and C481S-BTK. Selectivity of ARQ 531 was assessed using a large kinase panel. Inhibition of wild-type BTK (wtBTK) and C481S mutant (mBTK) forms by ARQ 531 was determined using in vitro assays. As a non-covalent BTK inhibitor it now rivals Arqule’s ARQ 531, and investors will be well aware that based on a much smaller dataset Arqule was sold to Merck & Co for 2.7bn. Moreover, compound 3e suppressed the cell growth more potently than the small molecule inhibitors ibrutinib and ARQ-531 in several cells. Nemtabrutinib (ARQ 531) 99. ARQ 531 is an ATP-competitive, potent reversible inhibitor of BTK, discovered by structure-based drug design approach. 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. However, the poor metabolic stability of PROTAC 6e have limited its further in vivo studies. ARQ 531 is not metabolized by any of the major drug metabolizing CYP450 enzymes. BTK is a key regulator of the B cell receptor (BCR) signaling pathway that mediates signaling from the cell surface to the cytoplasm and into the nucleus. 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. Background: ARQ 531 is a novel, ATP competitive reversible inhibitor Bruton's tyrosine kinase (BTK). ARQ 531 (MK-1026) is a reversible non-covalent and orally active inhibitor of Brutons Tyrosine Kinase (BTK), with IC50s of 0.85 nM and 0.39 nM for WT-BTK. 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.
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