TYD-68 is a CRBN -recruiting TYK2 PROTAC degrader with a DC50 of 0.42 nM, and displays selectivity against JAK1/JAK2 -dependent signaling pathways. TYD-68 inhibits TYK2 -mediated signaling, exerts therapeutic efficacy in murine psoriasis models, reduces PASI scores, downregulates TYK2 protein levels and decreases the secretion of proinflammatory cytokines, TYD-68 can be used for the study of psoriasis and other TYK2 -driven autoimmune diseases [1]. (Pink: Tyk2 ligand; Blue: Cereblon ligand; Black: linker ).
In Vivo, TYD-68 (compound 15t) (5 mg/kg; i.p.; once daily for 7 days) significantly ameliorates IMQ-induced psoriasis in mice, reduces PASI scores, TYK2 protein expression in skin, Th17 cell infiltration, and proinflammatory cytokines (IL-17, IL-23, IFN-α) in serum and skin tissues, without affecting body weight[1].
In Vitro, TYD-68 (compound 15t) (0.01-300 nM; 10 h) degrades TYK2 in Jurkat cells with a DC50 of 0.42 nM and a Dmax of 95%[1]. TYD-68 (1-100 nM; 10 h) selectively degrades TYK2 without affecting JAK1, JAK2, or JAK3 protein levels in Jurkat cells[1]. TYD-68 (30 nM; 4 h) shows proteome-wide degradation selectivity for TYK2 over 6873 detected proteins, with no downregulation of Ikaros or Aiolos[1]. TYD-68 (10 nM; 2-36 h) induces rapid and sustained TYK2 degradation, with significant degradation observed at 4 h and maximal degradation (~90%) at 10 h persisting up to 36 h[1]. TYD-68 (10 nM; 24 h treatment + 24 h washout) shows reversible and long-lasting TYK2 degradation[1]. TYD-68 (5 nM; 10 h) degradation of TYK2 is blocked by pre-treatment with Thalidomide or Deucravacitinib [1]. TYD-68 (5 nM; 10 h) degradation of TYK2 is abolished by pre-treatment with MG-132, Bortezomib, or Pevonedistat (MLN4924) [1]. TYD-68 (10 nM; 10 h) combined with Cycloheximide (CHX) significantly reduces TYK2 protein stability, decreasing the half-life of TYK2[1]. TYD-68 (0.1-1000 nM; 1 h pre-incubation + 1 h stimulation) inhibits IL-12-induced STAT4 phosphorylation in CD4+ T cells of human PBMCs with an IC50 of 8.6 nM, and inhibits IFN-α-induced STAT1 phosphorylation in Jurkat cells with an IC50 of 6.7 nM[1].
References:
[1]. Xiong S, et al. Discovery of a Highly Potent and Selective Tyrosine Kinase 2 (TYK2) Degrader with In Vivo Therapeutic Efficacy in a Murine Psoriasis Model. Journal of medicinal chemistry. 2025 Apr 10;68(7):7560-7578.
In Vivo, TYD-68 (compound 15t) (5 mg/kg; i.p.; once daily for 7 days) significantly ameliorates IMQ-induced psoriasis in mice, reduces PASI scores, TYK2 protein expression in skin, Th17 cell infiltration, and proinflammatory cytokines (IL-17, IL-23, IFN-α) in serum and skin tissues, without affecting body weight[1].
In Vitro, TYD-68 (compound 15t) (0.01-300 nM; 10 h) degrades TYK2 in Jurkat cells with a DC50 of 0.42 nM and a Dmax of 95%[1]. TYD-68 (1-100 nM; 10 h) selectively degrades TYK2 without affecting JAK1, JAK2, or JAK3 protein levels in Jurkat cells[1]. TYD-68 (30 nM; 4 h) shows proteome-wide degradation selectivity for TYK2 over 6873 detected proteins, with no downregulation of Ikaros or Aiolos[1]. TYD-68 (10 nM; 2-36 h) induces rapid and sustained TYK2 degradation, with significant degradation observed at 4 h and maximal degradation (~90%) at 10 h persisting up to 36 h[1]. TYD-68 (10 nM; 24 h treatment + 24 h washout) shows reversible and long-lasting TYK2 degradation[1]. TYD-68 (5 nM; 10 h) degradation of TYK2 is blocked by pre-treatment with Thalidomide or Deucravacitinib [1]. TYD-68 (5 nM; 10 h) degradation of TYK2 is abolished by pre-treatment with MG-132, Bortezomib, or Pevonedistat (MLN4924) [1]. TYD-68 (10 nM; 10 h) combined with Cycloheximide (CHX) significantly reduces TYK2 protein stability, decreasing the half-life of TYK2[1]. TYD-68 (0.1-1000 nM; 1 h pre-incubation + 1 h stimulation) inhibits IL-12-induced STAT4 phosphorylation in CD4+ T cells of human PBMCs with an IC50 of 8.6 nM, and inhibits IFN-α-induced STAT1 phosphorylation in Jurkat cells with an IC50 of 6.7 nM[1].
References:
[1]. Xiong S, et al. Discovery of a Highly Potent and Selective Tyrosine Kinase 2 (TYK2) Degrader with In Vivo Therapeutic Efficacy in a Murine Psoriasis Model. Journal of medicinal chemistry. 2025 Apr 10;68(7):7560-7578.