Pyridone 6 (Synonyms: CMP 6, JanusAssociated Kinase Inhibitor I, Pyridone 6)

Pyridone 6 inhibits Jak3 with K(I)=5 nM; Pyridone 6 also inhibits Jak family members Tyk2 and Jak2 with IC(50)=1 nM and Jak1 with IC(50)=15 nM. Pyridone 6 was tested as an inhibitor of 21 other protein kinases; it inhibited these kinases with IC(50)s ranging from 130 nM to 10 μM^[1].

Pyridone 6 strongly inhibited Th2 and modestly inhibited Th1, whereas it enhanced Th17 development when present within a certain range of concentrations. This is mostly due to strong suppression of the IFN-γ/STAT1, IL-2/STAT5, and IL-4/STAT6 signaling pathways by Pyridone 6, which all inhibit Th17 differentiation, as well as modest suppression of IL-6/STAT3, which is essential for Th17 differentiation^[2，5].

In mice, Mean outward current decreased by 44% in WIF-B hepatoma cells incubated with the established hepatic differentiating factors oncostatin M/dexamethasone for 1-8 days. Pre-incubation with pyridone 6, a pan-JAK inhibitor, blocked the current reduction^[3]. Pyridone 6 blocks IL2 and IL4 dependent proliferation of CTLL cells and inhibits the phosphorylation of STAT5 as measured by Western blotting^[1]. Pyridone 6 is a more sensitive and specific inhibitor of JAK-STAT3 activity compared with AG490 and potently inhibited the growth of primary myeloma cells and myeloma-derived cell lines grown on BMSCs^[4]. Inhibition of JAK by pyridone 6 resulted in the suppression of STAT3 phosphorylation and secretion of a subset of chemokines and JAK-activating cytokines^[6]. Cytomix-induced STAT1 activation was lower and CXCR3 ligand mRNA production was more sensitive to Pyridone 6 and AG-490 in asthmatic than nonasthmatic ASMCs, but CXCL10/CXCL11 release was inhibited by the same proportion^[7].

References:
[1]. Thompson JE, Cubbon RM, et,al. Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23. doi: 10.1016/s0960-894x(02)00106-3. PMID: 11934592
[2]. Nakagawa R, Yoshida H, et,al. Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17. J Immunol. 2011 Nov 1;187(9):4611-20. doi: 10.4049/jimmunol.1100649. Epub 2011 Sep 28. PMID: 21957150.
[3]. Ogunrinde A, Pereira RD, et,al. Hepatocellular differentiation status is characterized by distinct subnuclear localization and form of the chanzyme TRPM7. Differentiation. 2017 Jul-Aug;96:15-25. doi: 10.1016/j.diff.2017.06.001. Epub 2017 Jun 12. PMID: 28609676.
[4]. Pedranzini L, Dechow T, et,al.Pyridone 6, a pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells. Cancer Res. 2006 Oct 1;66(19):9714-21. doi: 10.1158/0008-5472.CAN-05-4280. PMID: 17018630.
[5]. Mangan PR, Harrington LE, et,al.Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006 May 11;441(7090):231-4. doi: 10.1038/nature04754. Epub 2006 Apr 30. PMID: 16648837.
[6]. Ohno T, Aoki H, et,al. Cytokine Profile of Human Abdominal Aortic Aneurysm: Involvement of JAK/STAT Pathway. Ann Vasc Dis. 2018 Mar 25;11(1):84-90. doi: 10.3400/avd.oa.17-00086. PMID: 29682112; PMCID: PMC5882349.
[7]. Tan X, Alrashdan YA, et,al. Airway smooth muscle CXCR3 ligand production: regulation by JAK-STAT1 and intracellular Ca2?. Am J Physiol Lung Cell Mol Physiol. 2013 Jun 1;304(11):L790-802. doi: 10.1152/ajplung.00356.2012. Epub 2013 Apr 5. PMID: 23564506.