Abstract
Bruton's tyrosine kinase (BTK) plays a vital role in mature B-cell proliferation, development and function. Its inhibitors have gradually been applied for the treatment of many B-cell malignancies. However, because of treatment-associated drug resistance or low efficacy, it is urgent to develop new inhibitors and/or improve the efficacy of current inhibitors, where finding the intrinsic activation mechanism becomes the key to solve this problem. Here, we used BTK T474M mutation as a resistance model for inhibitors to study the mechanism of BTK activation and drug resistance by free molecular dynamics simulations. The results showed that the increase of kinase activity of T474M mutation is coming from the conformation change of the activation ring and ATP binding sites located in BTK N-terminus region. Specifically, the Thr474 mutation changed the structure of A-loop and stabilized the binding site of ATP, thus promoting the catalytic ability in the kinase domain. This localized dynamics-driven activation mechanism and resistance mechanism of BTK may provide new ideas for drug development in B-cell malignancies.
Highlights
Many protein kinases are considered key molecules in cancer, and they constitute major drug targets since certain kinase signalling pathways are functionally essential for many types of cancer [1]
We calculated the Cα root mean square fluctuation (RMSF) value for each residue in the kinase domain and found that the mutation promoted skeleton mobility, with the most obvious fluctuation occurring at the C-terminus of the activation loop (A-loop)
We found an increase in the radius of gyration (Rgyr) of the A-loop in the mutant compared to the WT kinase domain, remarkably reflecting the internal structural change of the mutant
Summary
Many protein kinases are considered key molecules in cancer, and they constitute major drug targets since certain kinase signalling pathways are functionally essential for many types of cancer [1]. The US Food and Drug Administration (FDA) has approved many kinase inhibitors for the treatment of multiple solid and haematological tumours [2,3]. Bruton’s tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, is the only member of the Tec family of kinases that has been related to the pathogenesis of cancer in humans [4]. A firstgeneration inhibitor of BTK, was approved in 2013 and has shown noteworthy clinical activity in lymphoid malignancies, such as chronic lymphocytic leukaemia (CLL) [5] and mantle cell lymphoma (MCL) [6].
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