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. 2024 Nov 15:114:117932.
doi: 10.1016/j.bmc.2024.117932. Epub 2024 Sep 30.

Design of a potent and selective dual JAK1/TYK2 inhibitor

Oscar Mammoliti  1 , Christel Menet  1 , Céline Cottereaux  2 , Javier Blanc  1 , Ann De Blieck  1 , Ghjuvanni Coti  1 , Raphaël Geney  2 , Line Oste  1 , Koen Ostyn  1 , Adeline Palisse  1 , Evelyne Quinton  1 , Benoit Schmitt  1 , Monica Borgonovi  2 , Isabelle Parent  2 , Catherine Jagerschmidt  2 , Steve De Vos  1 , Béatrice Vayssiere  2 , Miriam López-Ramos  2 , Kenji Shoji  2 , Reginald Brys  1 , David Amantini  2 , René Galien  2 , Caroline Joannesse  3
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Free article

Design of a potent and selective dual JAK1/TYK2 inhibitor

Oscar Mammoliti et al. Bioorg Med Chem. .
Free article

Abstract

Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of TH1 and TH17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23-induced psoriasis-like inflammation mouse model.

Keywords: Autoimmune disease; High-throughput screening; Inflammatory disease; Janus kinase; Selective inhibitor; Tyrosine kinase.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors were employees of Galapagos at the time of the work. Ghjuvanni Coti, Line Oste, Steve De Vos, Miriam López-Ramos, René Galien, and Caroline Joannesse are employees of Galapagos. Raphaël Geney was an employee of Galapagos at the time of the study and is now an employee of Cabinet Nony. Céline Cottereaux, Isabelle Parent, Catherine Jagerschmidt and Béatrice Vayssiere were employees of Galapagos at the time of the study and are now employees of NovAliX. Oscar Mammoliti was an employee of Galapagos at the time of the study and is now an employee of Janssen. Christel Menet and Ann De Blieck were employees of Galapagos at the time of the study and are now employees of Confo Therapeutics. Javier Blanc was an employee of Galapagos at the time of the study and is now an employee of Farmacia Blanc CB. Koen Ostyn was an employee of Galapagos at the time of the study and is now an employee of FOD Financiën - SPF Finances. Adeline Palisse was an employee of Galapagos at the time of the study and is now an employee of Acerta Pharma B.V. Evelyne Quinton was an employee of Galapagos at the time of the study and is now an employee of AGC Pharma Chemicals Europe. Benoit Schmitt, Monica Borgonovi, and David Amantini were employees of Galapagos at the time of the study. Reginald Brys was an employee of Galapagos at the time of the study and is now an employee of Agomab Therapeutics. Kenji Shoji was an employee of Galapagos at the time of the study and is now an employee of Oncodesign Precision Medicine.

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