PUBLICATION
Selective Inhibition of Bruton's Tyrosine Kinase by a Designed Covalent Ligand Leads to Potent Therapeutic Efficacy in Blood Cancers Relative to Clinically Used Inhibitors
- Authors
- Sousa, B.B., de Almeida, C.R., Barahona, A.F., Lopes, R., Martins-Logrado, A., Cavaco, M., Neves, V., Carvalho, L.A.R., Labão-Almeida, C., Coelho, A.R., Leal Bento, M., Lopes, R.M.R.M., Oliveira, B.L., Castanho, M.A.R.B., Neumeister, P., Deutsch, A., Vladimer, G.I., Krall, N., João, C., Corzana, F., Seixas, J.D., Fior, R., Bernardes, G.J.L.
- ID
- ZDB-PUB-221122-13
- Date
- 2022
- Source
- ACS pharmacology & translational science 5: 1156-1168 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 36407952 Full text @ ACS Pharmacol Transl Sci
Citation
Sousa, B.B., de Almeida, C.R., Barahona, A.F., Lopes, R., Martins-Logrado, A., Cavaco, M., Neves, V., Carvalho, L.A.R., Labão-Almeida, C., Coelho, A.R., Leal Bento, M., Lopes, R.M.R.M., Oliveira, B.L., Castanho, M.A.R.B., Neumeister, P., Deutsch, A., Vladimer, G.I., Krall, N., João, C., Corzana, F., Seixas, J.D., Fior, R., Bernardes, G.J.L. (2022) Selective Inhibition of Bruton's Tyrosine Kinase by a Designed Covalent Ligand Leads to Potent Therapeutic Efficacy in Blood Cancers Relative to Clinically Used Inhibitors. ACS pharmacology & translational science. 5:1156-1168.
Abstract
Bruton's tyrosine kinase (BTK) is a member of the TEC-family kinases and crucial for the proliferation and differentiation of B-cells. We evaluated the therapeutic potential of a covalent inhibitor (JS25) with nanomolar potency against BTK and with a more desirable selectivity and inhibitory profile compared to the FDA-approved BTK inhibitors ibrutinib and acalabrutinib. Structural prediction of the BTK/JS25 complex revealed sequestration of Tyr551 that leads to BTK's inactivation. JS25 also inhibited the proliferation of myeloid and lymphoid B-cell cancer cell lines. Its therapeutic potential was further tested against ibrutinib in preclinical models of B-cell cancers. JS25 treatment induced a more pronounced cell death in a murine xenograft model of Burkitt's lymphoma, causing a 30-40% reduction of the subcutaneous tumor and an overall reduction in the percentage of metastasis and secondary tumor formation. In a patient model of diffuse large B-cell lymphoma, the drug response of JS25 was higher than that of ibrutinib, leading to a 64% "on-target" efficacy. Finally, in zebrafish patient-derived xenografts of chronic lymphocytic leukemia, JS25 was faster and more effective in decreasing tumor burden, producing superior therapeutic effects compared to ibrutinib. We expect JS25 to become therapeutically relevant as a BTK inhibitor and to find applications in the treatment of hematological cancers and other pathologies with unmet clinical treatment.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping