AI Article Synopsis
- BTK is crucial in B cell signaling and is a target for treating B cell cancers and immune diseases; however, covalent inhibitors face challenges due to the C481S mutation in most patients.
- The FDA's 2023 approval of Pirtobrutinib sparked interest in developing non-covalent, reversible BTK inhibitors, leading to the design of 11 candidates in this study.
- Among these, WS-11 demonstrated the highest effectiveness with low IC values for both wild type and C481S mutation BTK, showing promising drug-like properties for future development.
Article Abstract
Bruton's Tyrosine Kinase (BTK) played a key role in the B cell antigen receptor (BCR) signaling pathway, and was considered a hotspot in the treatment of B cell malignant tumors and B cell immune diseases. There were 5 covalent irreversible inhibitors launched currently on the market, but C481S mutation was detected in most patients after administration. The approval of Pirtobrutinib (Jaypirca) by FDA in 2023 aroused great interest in the development of non-covalent and reversible BTK inhibitors. In order to solve the resistance of covalent irreversible inhibitors caused by C481S mutation, 11 reversible BTK inhibitors were designed based on screening in this article. The design, synthesis, in silico studies, and in vitro evaluations were performed for further verification. Among them, compound WS-11 showed best activity with IC of 3.9 nM for wild type, 2.2 nM for C481S mutation BTK, which was comparable to the positive control Pirtobrutinib. Furthermore, WS-11 would have a good druglikeness properties predicted by pkCSM and SwissADME, which provided a promising lead for further optimization and development.
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| http://dx.doi.org/10.1016/j.cbi.2024.111241 | DOI Listing |
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