CC-930

• CAT Number: I005384
• CAS Number: 899805-25-5
• Molecular Formula: C21H23F3N6O2
• Molecular Weight: 448.4
• Purity: ≥95%
• Synonyms: 4-[[9-[(3S)-oxolan-3-yl]-8-(2,4,6-trifluoroanilino)purin-2-yl]amino]cyclohexan-1-ol
• Target: JNK
• Solubility: DMSO: ≥ 33 mg/mL
• Storage: Store at -20°C
• IC50: 61 nM (JNK1); 7 nM (JNK2); 6 nM (JNK3) [1]
• InChIKey: IBGLGMOPHJQDJB-IHRRRGAJSA-N

CC-930(Tanzisertib) is a selective and potent JNK1/JNK2/JNK3(IC50=61/7/6 nM) inhibitor and is currently under clinical development for fibrotic and infammatory indications.IC50 Value: 61 nM (JNK1); 7 nM (JNK2); 6 nM (JNK3) [1]Target: JNK1/2/3in vitro: Compound 1 (CC-930) showed remarkable selectivity in a panel of 240 kinases, EGFR being the only non-MAP kinase inhibited more than 50% at 3 lM (IC50 = 0.38 lM). It inhibited no receptor at greater than 50% at 10 lM concentration in a panel of 75 receptors, ion channels and neurotransmitter transporters. Finally, when tested against 22 diverse non-kinase enzymes at 10 lM, no inhibition greater than 50% was observed [1]. Incubation with CC-930 prevented the phosphorylation of c-Jun and reduced the stimulatory levels of these cytokines on the release of collagen [2].in vivo: Inhibition of JNK by CC-930 prevented dermal thickening, myofibroblast differentiation and the accumulation of collagen in a dose-dependent manner in mice challenged with bleomycin and in TSK1 mice. In addition to the prevention of fibrosis, treatment with pharmacologically relevant doses of CC-930 also induced regression of established experimental fibrosis [2]. CC-930 did not affect blood pressure, kidney hypertrophy, glomerular hyperfiltration, podocyte loss, glomerular fibrosis or tubulointerstitial injury in diabetic SHR (spontaneously hypertensive rats). However, CC-930 reduced macrophages and ccl2 mRNA levels in diabetic kidneys [3].Toxicity: There were no deaths or AEs that led to withdrawal during the study. Fifteen (33%) subjects reported a total of 22 treatment-emergent adverse events (TEAEs). Subject 207 (25-mg CC-930 group) was involved in a road traffic accident 6 days after the dose and was hospitalized. This adverse event was considered as a serious adverse event but not related to the study drug. The severity of all other adverse events was rated as mild [4].

Reference

1:Bioorg Med Chem Lett. 2012 Feb 1;22(3):1433-8. doi: 10.1016/j.bmcl.2011.12.027. Epub 2011 Dec 10. Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor.Plantevin Krenitsky V,Nadolny L,Delgado M,Ayala L,Clareen SS,Hilgraf R,Albers R,Hegde S,D/’Sidocky N,Sapienza J,Wright J,McCarrick M,Bahmanyar S,Chamberlain P,Delker SL,Muir J,Giegel D,Xu L,Celeridad M,Lachowitzer J,Bennett B,Moghaddam M,Khatsenko O,Katz J,Fan R,Bai A,Tang Y,Shirley MA,Benish B,Bodine T,Blease K,Raymon H,Cathers BE,Satoh Y, PMID: 22244937 DOI: 10.1016/j.bmcl.2011.12.027 Abstract: In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.Copyright © 2011 Elsevier Ltd. All rights reserved.