TYK2-IN-12

TYK2-IN-12 (compound 30) is an orally active, potent and selective TYK2 (tyrosine kinase 2) inhibitor, with a Ki of 0.51 nM. TYK2-IN-12 inhibits IL-12 induced IFNγ, with IC50 values of 2.7 and 7.0 μM in human and mouse whole blood, respectively. TYK2-IN-12 can be used for psoriasis research[1].

Signaling Pathways >> JAK/STAT Signaling >> JAK

Signaling Pathways >> Epigenetics >> JAK

Signaling Pathways >> Stem Cell/Wnt >> JAK

Signaling Pathways >> Immunology/Inflammation >> IFNAR

Research Areas >> Inflammation/Immunology

Tyk2:0.51 nM (Ki)

JAK3:6.63 nM (Ki)

JAK2:21.93 nM (Ki)

JAK1:45.9 nM (Ki)

TYK2-IN-12 (compound 30) shows 90, 43, and 13-fold selectivity over JAK1, JAK2, and JAK3, respectively[1]. TYK2-IN-12 exhibits excellent selectivity over hERG (IC50 > 30 μM) and over a panel of 10 cytochrome P450 enzymes (IC50s > 30 μM against CYP450s 3A4, 3D6, 2C9, 2C8, 1A2, 2A6, 2B6, 2C19, 2E1, and 3A5)[1]. TYK2-IN-12 shows cell-based potency and selectivity in human PBMC by blockade of IL-12 induced phospho-STAT4, GM-CSF induced phospho-STAT5, and IL-2 induced phospho-STAT5, with IC50 values of 0.10 μM, 4.1 μM and 0.25 μM, respectively[1].

TYK2-IN-12 (compound 30) (0-100 mg/kg, PO, daily for 10 days) dose-dependently reduces immune responses[1]. TYK2-IN-12 (3 mg/kg (IV), 10 mg/kg (PO), once) shows moderate clearance and volumes of distribution, and exhibits moderate to good oral absorption[1]. Pharmacokinetic Parameters of TYK2-IN-12 in male C57Bl/6 mice and smale Sprague-Dawley rats[1]. Species Mouse Rat PPB Fumax (h) 0.061 0.10 CL (mL/min/kg) 28 27 t1/2 (h) 1.8 1.6 Vd (L/kg) 1.2 1.9 F (%) >90 32 Animal Model: C57BL/6 mice (IL-23 induced inflammation model)[1] Dosage: 0, 10, 30, and 100 mg/kg Administration: PO, daily for 10 days Result: Dose-dependently reduced immune responses, with up to 74 % inhibition of ear swelling and 96 % inhibition of tissue levels of IL-17A at 100 mg/kg, highlighting the crucial role of TYK2 in IL-23 induced IL-17 and tissue inflammation. Exhibited improved skin histology and a dose-dependent reduction of spleen weight. Animal Model: Male C57Bl/6 mice, male SD rats[1] Dosage: 3 mg/kg (IV), 10 mg/kg (PO) Administration: IV or PO, once (Pharmacokinetic Analysis) Result: Showed moderate clearance and volumes of distribution of 1.2 L/Kg and 1.9 L/Kg, respectively in mouse and rat IV PK, and exhibited moderate to good oral absorption, with oral bioavailabilities of 32-100%.

[1]. Leit S, et al. Potent and selective TYK2-JH1 inhibitors highly efficacious in rodent model of psoriasis. Bioorg Med Chem Lett. 2022 Jul 13;73:128891.