JNJ-7706621
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MedKoo CAT#: 406161

CAS#: 443797-96-4

Description: JNJ-7706621 is a novel cell cycle inhibitor that showed potent inhibition of several cyclin-dependent kinases (CDK) and Aurora kinases and selectively blocked proliferation of tumor cells of various origins but was about 10-fold less effective at inhibiting normal human cell growth in vitro. In human cancer cells, treatment with JNJ-7706621 inhibited cell growth independent of p53, retinoblastoma, or P-glycoprotein status; activated apoptosis; and reduced colony formation. At low concentrations, JNJ-7706621 slowed the growth of cells and at higher concentrations induced cytotoxicity.


Chemical Structure

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JNJ-7706621
CAS# 443797-96-4

Theoretical Analysis

MedKoo Cat#: 406161
Name: JNJ-7706621
CAS#: 443797-96-4
Chemical Formula: C15H12F2N6O3S
Exact Mass: 394.06597
Molecular Weight: 394.36
Elemental Analysis: C, 45.68; H, 3.07; F, 9.64; N, 21.31; O, 12.17; S, 8.13

Price and Availability

Size Price Availability Quantity
10.0mg USD 120.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1250.0 Ready to ship
500.0mg USD 1950.0 Ready to ship
1.0g USD 2950.0 Ready to ship
2.0g USD 5250.0 Ready to ship
10.0mM * 1 mL DMSO USD 190.0 Ready to ship
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Synonym: JNJ7706621; JNJ 7706621; JNJ-7706621

IUPAC/Chemical Name: 4-((5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl)amino)benzenesulfonamide

InChi Key: KDKUVYLMPJIGKA-UHFFFAOYSA-N

InChi Code: InChI=1S/C15H12F2N6O3S/c16-10-2-1-3-11(17)12(10)13(24)23-14(18)21-15(22-23)20-8-4-6-9(7-5-8)27(19,25)26/h1-7H,(H2,19,25,26)(H3,18,20,21,22)

SMILES Code: O=S(C1=CC=C(NC2=NN(C(C3=C(F)C=CC=C3F)=O)C(N)=N2)C=C1)(N)=O

Appearance: Solid powder

Purity: >98%

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, not in water

Shelf Life: >5 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

Biological target: JNJ-7706621 is a potent aurora kinase inhibitor, and also inhibits CDK1 and CDK2, with IC50s of 9 nM, 3 nM, 11 nM, and 15 nM for CDK1, CDK2, aurora-A and aurora-B, respectively.
In vitro activity: The inhibitor arrested various cells at G2 phase at low concentration, and at both G1 and G2 phases at high concentration. JNJ-7706621 did not prevent localization of Aurora A to the spindle poles, but did inhibit other centrosomal proteins such as TOG, Nek2, and TACC3 in early mitotic phase. Similarly, the drug did not prevent localization of Aurora B to the kinetochore, but did inhibit other chromosomal passenger proteins such as Survivin and INCENP. In the cells exposed to JNJ-7706621 after nocodazole release, Aurora B, INCENP, and Survivin became relocated to the peripheral region of chromosomes, but Plk1 and Prc1 were localized on microtubules in later mitotic phase. Treatment of nocodazole-synchronized cells with JNJ-7706621 was able to override mitotic arrest by preventing spindle checkpoint signaling, resulting in failure of chromosome alignment and segregation. Injection of the drug significantly inhibited the growth of TC135 Ewing's sarcoma cells transplanted into athymic mice by cell cycle arrest and apoptosis. JNJ-7706621 is a unique inhibitor regulating cell cycle progression at multiple points, suggesting that it could be useful for cell cycle analysis and therapy of various cancers, including Ewing's sarcoma. Reference: Curr Cancer Drug Targets. 2012 Jul;12(6):625-39. https://www.eurekaselect.com/98883/article
In vivo activity: The antitumor efficacy of JNJ-7706621 was examined in an A375 melanoma human tumor xenograft model. Two dose levels, 100 and 125 mg/kg, were evaluated and mean tumor size was calculated from six animals per group. Figure 4A shows tumor sizes for the 125 mg/kg dose under various schedules. Daily dosing was the most efficacious and caused tumor regression; however, this schedule could only be tolerated for 22 days before toxicity emerged (Table 2). There were five treatment-related deaths in this dose group; all occurred between days 22 and 39 and were not preceded by detectable weight loss. The 7 on/7 off schedule was nearly as effective as the daily dosing regimen with 93% tumor growth inhibition (TGI) and all animals survived to the end of the study ( Fig. 4A; Table 2). The next most effective schedule at 125 mg/kg was 7 on/14 off (88% TGI) followed by Q3D and Q4D, with 69% and 43% TGI, respectively, and all these schedules were well tolerated (Fig. 4A; Table 2). Identical dosing schedules were applied to evaluate the 100 mg/kg dose and the same pattern of efficacy was observed (Table 2). Several schedules and dose combinations resulted in equivalent efficacy. For example, the 125 mg/kg 7 on/7 off schedule and the 100 mg/kg QD schedule produced identical TGI values of 93% (Fig. 4B; Table 2). Figure 4C compares two different dosing schedules at the same dose level. Tumor growth was nearly flat under the QD regimen, whereas under the 7 on/7 off schedule, a pattern of tumor inhibition and regrowth was observed. A reduction in tumor size was apparent during periods of dosing (days 1-7, 14-21, and 29-35), and tumor regrowth was observed during periods of nondosing (days 8-14, 22-28, and 36-41). However, at a slightly higher dose level of 125 mg/kg but under the same schedule of 7 on/7 off, there was a persistent effect evident during dosing holidays with very little tumor regrowth ( Fig. 4B). Analysis of the relationship between tumor size and dose indicates that the amount of inhibition of tumor growth was proportional to the total cumulative dose, regardless of the schedule. Figure 4D shows the average tumor size versus the total cumulative dose calculated on day 11 of the study. This relationship held true for analysis done at any time during the study (data not shown). These results identify suitable dosing regimens that could be applied in clinical trials. Reference: Cancer Res. 2005 Oct 1;65(19):9038-46. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16204078

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 79.0 200.32

Preparing Stock Solutions

The following data is based on the product molecular weight 394.36 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.

Recalculate based on batch purity %
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
In vitro protocol: 1. Matsuhashi A, Ohno T, Kimura M, Hara A, Saio M, Nagano A, Kawai G, Saitou M, Takigami I, Yamada K, Okano Y, Shimizu K. Growth suppression and mitotic defect induced by JNJ-7706621, an inhibitor of cyclin-dependent kinases and aurora kinases. Curr Cancer Drug Targets. 2012 Jul;12(6):625-39. doi: 10.2174/156800912801784839. PMID: 22463590. 2. Emanuel S, Rugg CA, Gruninger RH, Lin R, Fuentes-Pesquera A, Connolly PJ, Wetter SK, Hollister B, Kruger WW, Napier C, Jolliffe L, Middleton SA. The in vitro and in vivo effects of JNJ-7706621: a dual inhibitor of cyclin-dependent kinases and aurora kinases. Cancer Res. 2005 Oct 1;65(19):9038-46. doi: 10.1158/0008-5472.CAN-05-0882. PMID: 16204078.
In vivo protocol: 1. Emanuel S, Rugg CA, Gruninger RH, Lin R, Fuentes-Pesquera A, Connolly PJ, Wetter SK, Hollister B, Kruger WW, Napier C, Jolliffe L, Middleton SA. The in vitro and in vivo effects of JNJ-7706621: a dual inhibitor of cyclin-dependent kinases and aurora kinases. Cancer Res. 2005 Oct 1;65(19):9038-46. doi: 10.1158/0008-5472.CAN-05-0882. PMID: 16204078.

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1: Matsuhashi A, Ohno T, Kimura M, Hara A, Saio M, Nagano A, Kawai G, Saitou M, Takigami I, Yamada K, Okano Y, Shimizu K. Growth suppression and mitotic defect induced by JNJ-7706621, an inhibitor of cyclin-dependent kinases and aurora kinases. Curr Cancer Drug Targets. 2012 Jul;12(6):625-39. PubMed PMID: 22463590.

2: Pflug A, de Oliveira TM, Bossemeyer D, Engh RA. Mutants of protein kinase A that mimic the ATP-binding site of Aurora kinase. Biochem J. 2011 Nov 15;440(1):85-93. doi: 10.1042/BJ20110592. PubMed PMID: 21774789.

3: Danhier F, Ucakar B, Magotteaux N, Brewster ME, Préat V. Active and passive tumor targeting of a novel poorly soluble cyclin dependent kinase inhibitor, JNJ-7706621. Int J Pharm. 2010 Jun 15;392(1-2):20-8. doi: 10.1016/j.ijpharm.2010.03.018. Epub 2010 Mar 11. PubMed PMID: 20226846.

4: Seamon JA, Rugg CA, Emanuel S, Calcagno AM, Ambudkar SV, Middleton SA, Butler J, Borowski V, Greenberger LM. Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor. Mol Cancer Ther. 2006 Oct;5(10):2459-67. PubMed PMID: 17041089.

5: Huang S, Connolly PJ, Lin R, Emanuel S, Middleton SA. Synthesis and evaluation of N-acyl sulfonamides as potential prodrugs of cyclin-dependent kinase inhibitor JNJ-7706621. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3639-41. Epub 2006 May 6. PubMed PMID: 16682186.

6: Emanuel S, Rugg CA, Gruninger RH, Lin R, Fuentes-Pesquera A, Connolly PJ, Wetter SK, Hollister B, Kruger WW, Napier C, Jolliffe L, Middleton SA. The in vitro and in vivo effects of JNJ-7706621: a dual inhibitor of cyclin-dependent kinases and aurora kinases. Cancer Res. 2005 Oct 1;65(19):9038-46. PubMed PMID: 16204078.



Additional Information