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.

Autor:	Sousa BB; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal., de Almeida CR; Champalimaud Foundation, Avenida de Brasília, 1400-038, Lisbon, Portugal., Barahona AF; Champalimaud Foundation, Avenida de Brasília, 1400-038, Lisbon, Portugal., Lopes R; Champalimaud Foundation, Avenida de Brasília, 1400-038, Lisbon, Portugal., Martins-Logrado A; Champalimaud Foundation, Avenida de Brasília, 1400-038, Lisbon, Portugal., Cavaco M; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal., Neves V; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal., Carvalho LAR; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K., Labão-Almeida C; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal., Coelho AR; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal., Leal Bento M; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal.; Centro Hospitalar Lisboa Norte, Department of Hematology and Bone Marrow Transplantation, Avenida Prof. Egas Moniz, 1649-035 Lisbon, Portugal., Lopes RMRM; Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1600-277 Lisbon, Portugal., Oliveira BL; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal., Castanho MARB; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal., Neumeister P; Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, 8036 Graz, Austria., Deutsch A; Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, 8036 Graz, Austria., Vladimer GI; Exscientia, The Schrödinger Building, Oxford Science Park, Oxford OX4 4GE, U.K., Krall N; Exscientia, The Schrödinger Building, Oxford Science Park, Oxford OX4 4GE, U.K., João C; Champalimaud Foundation, Avenida de Brasília, 1400-038, Lisbon, Portugal., Corzana F; Centro de Investigación en Síntesis Química, Departamento de Química, Universidad de La Rioja, 26006 Logroño, Spain., Seixas JD; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal.; TARGTEX S.A., Avenida Tenente Valadim, N°17, 2F, 2560-275 Torres Vedras, Portugal., Fior R; Champalimaud Foundation, Avenida de Brasília, 1400-038, Lisbon, Portugal., Bernardes GJL; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal.; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2022 Nov 02; Vol. 5 (11), pp. 1156-1168. Date of Electronic Publication: 2022 Nov 02 (Print Publication: 2022).
DOI:	10.1021/acsptsci.2c00163
Abstrakt:	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. Competing Interests: The authors declare the following competing financial interest(s): J. D. S. and G. J. L. B. are inventors in a patent (WO2020245430A1) related to the findings reported in this manuscript. (© 2022 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu