Immunosuppressive effects of new thiophene-based KV1.3 inhibitors

Gubič, Špela; Montalbano, Alberto; Sala, Cesare; Becchetti, Andrea; Hendrickx, Louise Antonia; Theemsche, Kenny M. Van; Pinheiro-Junior, Ernesto Lopes; Altadonna, Ginevra Chioccioli; Peigneur, Steve; Ilaš, Janez; Labro, Alain J.; Pardo, Luis A.; Tytgat, Jan; Tomašič, Tihomir; Arcangeli, Annarosa; Mašič, Lucija Peterlin

doi:10.1016/j.ejmech.2023.115561

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Immunosuppressive effects of new thiophene-based K_V1.3 inhibitors

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Pardo, Luis A.
Research Group of Oncophysiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Citation

Gubič, Š., Montalbano, A., Sala, C., Becchetti, A., Hendrickx, L. A., Theemsche, K. M. V., et al. (2023). Immunosuppressive effects of new thiophene-based K_V1.3 inhibitors. European Journal of Medicinal Chemistry, 259: 115561. doi:10.1016/j.ejmech.2023.115561.

Cite as: https://hdl.handle.net/21.11116/0000-000D-751B-2

Abstract

Voltage-gated potassium channel K_V1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca²⁺ homeostasis. Here, we present the structure-activity relationship, K_V1.3 inhibition, and immunosuppressive effects of new thiophene-based K_V1.3 inhibitors with nanomolar potency on K⁺ current in T-lymphocytes and K_V1.3 inhibition on Ltk^- cells. The new K_V1.3 inhibitor trans-18 inhibited K_V1.3 -mediated current in phytohemagglutinin (PHA)-activated T-lymphocytes with an IC₅₀ value of 26.1 nM and in mammalian Ltk^- cells with an IC₅₀ value of 230 nM. The K_V1.3 inhibitor trans-18 also had nanomolar potency against K_V1.3 in Xenopus laevis oocytes (IC₅₀ = 136 nM). The novel thiophene-based K_V1.3 inhibitors impaired intracellular Ca²⁺ signaling as well as T-cell activation, proliferation, and colony formation.