Background
CC-930 is a potent and selective inhibitor of JNK1/JNK2/JNK3 with IC50 values of 61 nM, 7 nM and 6 nM respectively. [1]
JNKs (c-Jun N-terminal kinases) belong to kinases which were originally indentified. They bind to c-Jun then phosphorylate it on Ser-63 and Ser-73 which located in its transcriptional activation domain. JNKs belong to MAPK family. They contain ten isforms encoded by three genes: JNK1, JNK2 and JNK3. They are 46 KD or 55 KD protein. They play an important role in stress stimuli, such as heat shock, cytokines, and osmotic shock. They are also responsive to the cellular apoptosis pathway and T cell differentiation. They are activated through a dual phosphorylation of Thr and Tyr residues within a Thr-Pro-Tyr motif which located in kinase subdomain. JNKs modify the activity of many proteins that act in the nucleus reside or at the mitochondria. JNKs activate the downstream molecules which include p53, c-Jun, ELK1, SMAD4 and HSF1. JNKs regulate several important cellular functions, such as cell growth, survival, differentiation and apoptosis.[2]
CC-930 kinetically competitive with ATP in the phosphorylation of the substrate c-Jun against all isoforms of JNK with Ki values of 44 ± 3 nM (JNK1), 6.2 ± 0.6 nM and IC50 value of 5 nm for JNK3. EGFR is the only non-MAP kinase which inhibited more than 50% at 3 ?M. It did not inhibit greater than 50% against 22 diverse non-kinase enzymes at 10 M.[1] CC-930 reduced the phosphorylation of c-Jun the stimulated by TGF β at 1 μM which is a clinically relevant concentration in fi broblasts[3] CC-930 also was showed the potent antifibrotic founctions in the TSK1 model. CC-930 reduced hypodermal thickening with a dose-dependent manner by up to 85±4% in TSK1 mice.[3] CC-930 has no effect on kidney hypertrophy, blood pressur, podocyte loss, glomerular fibrosis in diabetic spontaneously hypertensive rats (SHR). However, CC-930 reduced the levels of ccl2 mRNA in diabetic kidneys[4].
参考文献:
[1].?? ?Plantevin Krenitsky V, Nadolny L, Delgado M, Ayala L, Clareen SS, Hilgraf R, Albers R, Hegde S, D'Sidocky N, Sapienza J et al: Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg Med Chem Lett, 22(3):1433-1438.
[2].?? ?Waetzig V, Herdegen T: Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage. Trends Pharmacol Sci 2005, 26(9):455-461.
[3].?? ?Reich N, Tomcik M, Zerr P, Lang V, Dees C, Avouac J, Palumbo K, Horn A, Akhmetshina A, Beyer C et al: Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis. Ann Rheum Dis, 71(5):737-745.
[4].?? ?Lim AK, Ma FY, Nikolic-Paterson DJ, Ozols E, Young MJ, Bennett BL, Friedman GC, Tesch GH: Evaluation of JNK blockade as an early intervention treatment for type 1 diabetic nephropathy in hypertensive rats. Am J Nephrol, 34(4):337-346.
Protocol
Cell experiment: | Systemic sclerosis (SSc) fibroblasts are incubated with 1 μM Tanzisertib (CC-930) in 96-well plates for 20 h. Then MTT is added at a final concentration of 1 mg/mL, and the cells are further incubated at 37°C for 4 h. Mock-treated fibroblasts are used as controls, and all other results are normalised to untreated cells. |
Animal experiment: | To evaluate the regression of fibrosis on inhibition of JNK, a modified model of bleomycin-induced dermal fibrosis is used. In this model, treatment is initiated 3 weeks after the beginning of the challenge with bleomycin, when significant dermal fibrosis is already established. The outcome of six different groups with a total number of 40 mice is analysed. The first group of mice receive subcutaneous injections of NaCl for 6 weeks. The second group is injected for 3 weeks with bleomycin followed by injections of NaCl for another 3 weeks to analyse the degree of fibrosis before treatment, and to control the spontaneous regression of fibrosis. The third group of mice is killed after 6 weeks of injections with bleomycin. The fourth and the fifth group are treated with Tanzisertib (CC-930) at doses of 50 mg/kg and 150 mg/kg for the last 3 weeks of continuous challenge with bleomycin for 6 weeks. The sixth group is a positive control group consisting of mice challenged with bleomycin for 6 weeks and treated in parallel with imatinib at doses of 50 mg/kg for the last 3 weeks. |
参考文献: [1]. Plantevin Krenitsky V, et al. Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg Med Chem Lett. 2012 Feb 1;22(3):1433-8.
[2]. Gan LT, et al. Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent. J Hepatol. 2014 Dec;61(6):1376-84.
[3]. Reich N, et al. Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis. Ann Rheum Dis. 2012 May;71(5):737-45.
[4]. Tavernier SJ, et al. Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival. Nat Cell Biol. 2017 Jun;19(6):698-710. |
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