Synonym
JNK Inhibitor X; BI-78D3; BI78D3; BI 78D3; c-Jun N-terminal Kinase Inhibitor X
IUPAC/Chemical Name
4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2,4-dihydro-5-[(5-nitro-2-thiazolyl)thio]-3H-1,2,4-triazol-3-one
InChi Key
QFRLDZGQEZCCJZ-UHFFFAOYSA-N
InChi Code
InChI=1S/C13H9N5O5S2/c19-11-15-16-12(25-13-14-6-10(24-13)18(20)21)17(11)7-1-2-8-9(5-7)23-4-3-22-8/h1-2,5-6H,3-4H2,(H,15,19)
SMILES Code
O=C1NN=C(SC2=NC=C([N+]([O-])=O)S2)N1C3=CC=C(OCCO4)C4=C3
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
JNK is a stress-activated protein kinase that modulates pathways implicated in a variety of disease states. JNK-interacting protein-1 (JIP1) is a scaffolding protein that enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. A minimal peptide region derived from JIP1 is able to inhibit JNK activity both in vitro and in cell.
Biological target:
BI-78D3 inhibits the JNK kinase activity with an IC50 of 280 nM.
In vitro activity:
As the ERK pathway regulates cell survival and proliferation1, the proliferation potential of cells following incubation with BI-78D3, with drug washout, was evaluated by monitoring their approach to confluence. Dose-dependent suppression of cell growth (IC50 ~ 3.5 µM) was noted when measured over 90 h (Fig. 4d). A similar treatment abrogated the formation of anchorage-dependent and anchorage-independent colonies (Fig. 4e). Cell cycle analysis revealed that treatment with BI-78D3 (6 µM), followed by washout for 24 and 48 h induced G1 arrest (Supplementary Fig. 17). Annexin V (Fig. 4f) and caspase3/7 assays (Fig. 4g) revealed significant dose-dependent induction of apoptosis 72 h after treatment, which is also evidenced by a significant induction of a sub-G1 population (Supplementary Fig. 18). Similar results were observed when BI-78D3 was not washed out.
Reference: Nat Commun. 2019 Nov 19;10(1):5232. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863825/
In vivo activity:
The effect of BI-78D3 on the growth of a BRAF-mutant xenograft model established from the human melanoma cell line A375 was evaluated. Inbred, athymic nude mice were injected with 1 × 106 A375 cells into the right flank. When tumors reached an average volume of 150 mm3, mice were randomized into two groups of ten mice each. One group was treated daily with an intraperitoneal injection of vehicle (2.5% ethanol, 5% Tween-80, 1× PBS), and the other group with 15 mg kg−1 BI-78D3 suspended in the vehicle. Tumor volumes were measured daily until tumors reached a maximum diameter of 1 cm. The tumor measurements of these mice were analyzed for tumor growth comparison (Fig. 5a) where BI-78D3 (15 mg kg−1 daily) caused potent tumor growth suppression after 10 days of treatment. BI-78D3 was tolerated by the mice, as measured by morbidity, lethality, and loss in body weight (Supplementary Fig. 23).
Reference: Nat Commun. 2019 Nov 19;10(1):5232. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863825/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMF |
33.0 |
86.99 |
| DMSO |
67.7 |
178.56 |
| DMSO:PBS (pH 7.2) (1:1) |
0.5 |
177.93 |
| Ethanol |
1.4 |
3.69 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
379.37
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Kaoud TS, Johnson WH, Ebelt ND, Piserchio A, Zamora-Olivares D, Van Ravenstein SX, Pridgen JR, Edupuganti R, Sammons R, Cano M, Warthaka M, Harger M, Tavares CDJ, Park J, Radwan MF, Ren P, Anslyn EV, Tsai KY, Ghose R, Dalby KN. Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo. Nat Commun. 2019 Nov 19;10(1):5232. doi: 10.1038/s41467-019-12996-8. PMID: 31745079; PMCID: PMC6863825.
In vitro protocol:
1. Kaoud TS, Johnson WH, Ebelt ND, Piserchio A, Zamora-Olivares D, Van Ravenstein SX, Pridgen JR, Edupuganti R, Sammons R, Cano M, Warthaka M, Harger M, Tavares CDJ, Park J, Radwan MF, Ren P, Anslyn EV, Tsai KY, Ghose R, Dalby KN. Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo. Nat Commun. 2019 Nov 19;10(1):5232. doi: 10.1038/s41467-019-12996-8. PMID: 31745079; PMCID: PMC6863825.
In vivo protocol:
1. Kaoud TS, Johnson WH, Ebelt ND, Piserchio A, Zamora-Olivares D, Van Ravenstein SX, Pridgen JR, Edupuganti R, Sammons R, Cano M, Warthaka M, Harger M, Tavares CDJ, Park J, Radwan MF, Ren P, Anslyn EV, Tsai KY, Ghose R, Dalby KN. Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo. Nat Commun. 2019 Nov 19;10(1):5232. doi: 10.1038/s41467-019-12996-8. PMID: 31745079; PMCID: PMC6863825.
1: Hein TW, Xu W, Xu X, Kuo L. Acute and Chronic Hyperglycemia Elicit JIP1/JNK-Mediated Endothelial Vasodilator Dysfunction of Retinal Arterioles. Invest Ophthalmol Vis Sci. 2016 Aug 1;57(10):4333-40. doi: 10.1167/iovs.16-19990. PubMed PMID: 27556216; PubMed Central PMCID: PMC5015966.
2: Alaseem AM, Madiraju P, Aldebeyan SA, Noorwali H, Antoniou J, Mwale F. Naproxen induces type X collagen expression in human bone-marrow-derived mesenchymal stem cells through the upregulation of 5-lipoxygenase. Tissue Eng Part A. 2015 Jan;21(1-2):234-45. doi: 10.1089/ten.TEA.2014.0148. Epub 2014 Oct 23. PubMed PMID: 25091567; PubMed Central PMCID: PMC4292866.
3: Posthumadeboer J, van Egmond PW, Helder MN, de Menezes RX, Cleton-Jansen AM, Beliën JA, Verheul HM, van Royen BJ, Kaspers GJ, van Beusechem VW. Targeting JNK-interacting-protein-1 (JIP1) sensitises osteosarcoma to doxorubicin. Oncotarget. 2012 Oct;3(10):1169-81. PubMed PMID: 23045411; PubMed Central PMCID: PMC3717953.
4: Strittmatter F, Walther S, Gratzke C, Göttinger J, Beckmann C, Roosen A, Schlenker B, Hedlund P, Andersson KE, Stief CG, Hennenberg M. Inhibition of adrenergic human prostate smooth muscle contraction by the inhibitors of c-Jun N-terminal kinase, SP600125 and BI-78D3. Br J Pharmacol. 2012 Jul;166(6):1926-35. doi: 10.1111/j.1476-5381.2012.01919.x. PubMed PMID: 22364229; PubMed Central PMCID: PMC3402815.
5: Stebbins JL, De SK, Machleidt T, Becattini B, Vazquez J, Kuntzen C, Chen LH, Cellitti JF, Riel-Mehan M, Emdadi A, Solinas G, Karin M, Pellecchia M. Identification of a new JNK inhibitor targeting the JNK-JIP interaction site. Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16809-13. doi: 10.1073/pnas.0805677105. Epub 2008 Oct 15. PubMed PMID: 18922779; PubMed Central PMCID: PMC2567907.
