VVD-118313 (compound 5a) is a potent, selective JAK1 inhibitor. VVD-118313 targets an isoform-restricted allosteric cysteine to block JAK1-dependent trans-phosphorylation and cytokine signaling. VVD-118313 can be used for research of cancer[1].
VVD-118313 (compound 5a; 0.01-10 μM; 3 h; primary human PBMCs) inhibits JAK1 by engagement of C817 and JAK2 by engagement of C838. VVD-118313 inhibits cysteine reactivity in a dose-dependent manner[1].
VVD-118313 (2 µM, 2h) blocks IFNα-simulated STAT1 and IL-6-stimulated STAT3 phosphorylation in WT- or C810A-JAK1-expressing 22Rv1 cells. VVD-118313 also blocks the constitutive phosphorylation of WT- and C810A-JAK1[1].
VVD-118313 (0.01-10 μM) selectively inhibits JAK1 signaling in primary human immune cells. VVD-118313 inhibits JAK1-dependent IFNα-pSTAT1, IL-6-pSTAT3, and IL-2-pSTAT5 pathways in human PBMCs in a dose-dependent manner[1].
VVD-118313 (0.1-0.4 μM; 24h) inhibits T-cell activation induction. VVD-118313 inhibits the activation of human T cells co-stimulated with αCD3/αCD28 by a reduction in the proportion of CD25+ T cells. VVD-118313 blocks the secretion of the Th1-polarizing cytokine IFNγ and increases the production of IL-2[1].
VVD-118313 (0.1-0.5 μM; 2h) inhibits on the production of pro-inflammatory cytokines and chemokines. VVD-118313 suppresses the induction of several pro-inflammatory chemokines, including CCL2/MCP-1, CXCL10/IP-10, and CCL4/MIP-1β[1].
Western Blot Analysis[1]
| Cell Line: | 22Rv1 cells |
| Concentration: | 0.01, 0.1, and 1 μM |
| Incubation Time: | 2 hours |
| Result: | Showed labeling of recombinant WT-JAK1 and C810A-JAK1, but not C817A-JAK1. |
Western Blot Analysis[1]
| Cell Line: | 22Rv1 cells |
| Concentration: | 2 µM |
| Incubation Time: | 2 hours |
| Result: | Inhibited WT- and C810A-JAK1 phosphorylation with even greater potency than STAT1/STAT3 phosphorylation. |
VVD-118313 (compound 5a; 25-50 mg/kg; i.h.; once; TYK2 knockout mice) inhibits JAK1 signaling in mice[1].
| Animal Model: | TYK2 knockout mice[1] |
| Dosage: | 25 and 50 mg/kg |
| Administration: | Subcutaneous injection; once |
| Result: | Revealed 75% engagement of JAK1_C816 at 25 and 50 mg/kg, while other JAK1 cysteines were unaffected in reactivity. |
[1]. Kavanagh ME, et, al. Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine. Nat Chem Biol. 2022 Sep 12.