Discovery of new non-covalent reversible BTK inhibitors: Synthesis, in silico studies, and in vitro evaluations
Zunyuan Wang1, Shu Wang2, Youkun Kang2
1Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310013, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, Hangzhou, 310013, China.
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 IC50 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.
Insights
New reversible Bruton's Tyrosine Kinase (BTK) inhibitors were developed to overcome resistance mutations. Compound WS-11 demonstrated potent activity against wild-type and C481S mutant BTK, showing promise for B cell malignancies.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- Bruton's Tyrosine Kinase (BTK) is crucial in B cell receptor signaling, making it a therapeutic target for B cell malignancies and immune diseases.
- Covalent irreversible BTK inhibitors face resistance due to the C481S mutation, necessitating novel therapeutic strategies.
- The development of non-covalent, reversible BTK inhibitors, like Pirtobrutinib, has gained traction.
Purpose of the Study:
- To design and synthesize novel reversible BTK inhibitors to overcome C481S mutation-induced resistance.
- To evaluate the in silico and in vitro efficacy of these novel compounds against wild-type and mutant BTK.
Main Methods:
- Computational screening and in silico studies were employed for inhibitor design.
- Synthesis of 11 novel reversible BTK inhibitors.
- In vitro evaluation of inhibitory activity against wild-type and C481S mutant BTK, and druglikeness prediction.
Main Results:
- Compound WS-11 exhibited potent inhibition against wild-type BTK (IC50 = 3.9 nM) and C481S mutant BTK (IC50 = 2.2 nM).
- WS-11's activity was comparable to the positive control, Pirtobrutinib.
- Predicted druglikeness properties of WS-11 suggest favorable pharmacokinetic profiles.
Conclusions:
- Compound WS-11 represents a promising lead candidate for developing next-generation reversible BTK inhibitors.
- WS-11 demonstrates potential for treating B cell malignancies resistant to current covalent inhibitors.
- Further optimization and development of WS-11 are warranted.
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