5-chloro-2-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-4-N-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine

• ChemBase ID: 72516
• Molecular Formular: C30H40ClN7O3S
• Molecular Mass: 614.2017
• Monoisotopic Mass: 613.26018686
• SMILES: c1cc(cc(c1Nc1ncc(c(n1)Nc1c(cccc1)S(=O)(=O)C(C)C)Cl)OC)N1CCC(CC1)N1CCN(CC1)C
• Canonical SMILES: COc1cc(ccc1Nc1ncc(c(n1)Nc1ccccc1S(=O)(=O)C(C)C)Cl)N1CCC(CC1)N1CCN(CC1)C
• InChI: InChI=1S/C30H40ClN7O3S/c1-21(2)42(39,40)28-8-6-5-7-26(28)33-29-24(31)20-32-30(35-29)34-25-10-9-23(19-27(25)41-4)37-13-11-22(12-14-37)38-17-15-36(3)16-18-38/h5-10,19-22H,11-18H2,1-4H3,(H2,32,33,34,35)
• InChIKey: QQWUGDVOUVUTOY-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 5-chloro-2-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-4-N-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine
• IUPAC Traditional name: 5-chloro-2-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-4-N-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine
• Synonyms: TAE684; NVP-TAE684

Database IDs

• CAS Number: 761439-42-3
• PubChem SID: 162037441
• PubChem CID: 16038120

CALCULATED PROPERTIES

• Acid pKa: 11.571996
• H Acceptors: 10
• H Donor: 2
• LogD (pH = 5.5): 1.3564507
• LogD (pH = 7.4): 3.004546
• Log P: 4.5492435
• Molar Refractivity: 170.157 cm^3
• Polarizability: 65.23537 Å^3
• Polar Surface Area: 102.93 Å^2
• Rotatable Bonds: 9
• Lipinski's Rule of Five: false

PROPERTIES

Physical Property

• Solubility: DMSO

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: ALK

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1108

Research Area

• Description: Cancer

Biological Activity

• Description: TAE684 is a potent and selective ALK inhibitor with IC50 of 3 nM.
• Targets: ALK
• IC50: 3 nM ^[1]
• In Vitro: TAE684 does not exhibit significant cross-reactivity against other kinases. TAE684 potently inhibits the proliferation of Ba/F3 NPM-ALK cells with IC50 of 3 nM, without affecting the survival of Ba/F3 cells even at 1 μM. TAE684 also inhibits proliferation of NPM-ALK-expressing human ALCL cell lines including Karpas-299 and SU-DHL-1 with IC50 of 2–5 nM. Molecular modeling reveals that L258 may be one of the major kinase-selectivity determinants for TAE684. TAE684 treatment results in a rapid and sustained inhibition of phosphorylation of NPM-ALK. TAE684 induces apoptosis and G1 phase arrest in NPM-ALK-expressing Ba/F3 cells and ALCL patient cell lines. ^[1] TAE684 markedly overcomes Crizotinib-resistance in H3122 CR cells, harboring the fusion oncogene EML4-ALK, decreasing cell growth, suppressing ALK phosphorylation and inducing apoptosis.^[2] Neurite outgrowth induced by expression of the mALK R1279Q mutant could be completely inhibited by TAE684 at 30 nM. ^[3]
• In Vivo: After 4 weeks of treatment with TAE684 at 3 and 10 mg/kg, there is a significant delay in lymphoma development and 100- to 1,000-fold reduction in luminescence signal, without any signs of compound- or disease-related toxicity in Karpas-299 lymphoma model. TAE684 treatment also induces disease regression in established Karpas-299 lymphomas and down-regulates CD30 expression. ^[1] TAE684 also shows impressive antitumor activity against H3122 CR xenograft tumors. ^[2] Furthermore, treatment with TAE684 improves the rough eye phenotype of both ALK mutants, especially that seen with ALKR1275Q, whereas Crizotinib has little effect on either phenotype. ^[3]

Protocol

• Protocol: Kinase Assay ^[1]
• In vitro Enzyme Assays.: All in vitro enzyme assays are done at Upstate Biotechnology with the exception of InsR and IGF1R. To determine the IC50 of TAE684 against InsR and IGF1R a homogeneous time-resolved fluorescence assay is performed. ATP (10 mM) and 20 mg/ml biotinylated PolyEY (Glu, Tyr 4:1) are combined with 50 nL of serial dilutions of TAE684 (10-500 nM) and 4 ng of InsR enzyme in the presence of the kinase reaction buffer (20 mM Tris×HCl, pH 7.5/10 mM MgCl₂/3 mM MnCl₂/1 mM DTT/10 mM NaVO₄/0.1 mg/ml of BSA). Assays are incubated for 1 hour at ambient temperature. Reactions are terminated by adding 10 mL of the detection solution containing 50 mM EDTA, 500 mM KF, 0.5 mg/ml of BSA, 5 mg/mL Eu3+ cryptate-labeled anti-phosphotyrosine antibody Mab PT66-K, and 5 mg/mL Streptavidin-XLent. The reaction is incubated for half an hour, and fluorescence signals are read on Analyst GT.
• Protocol: Cell Assay ^[1]
• Cell Lines: Luciferase-expressing Karpas-299, SU-DHL-1, and Ba/F3 cells and transformed Ba/F3 stably expressing NPM-ALK, Bcr-Abl, or TEL-kinase fusion constructs.
• Concentrations: 1 nM – 10 μM
• Incubation Time: 2–3 days
• Methods: Cells are seeded in 384-well plates (2.5×10^4 cells per well) and incubated with serial dilutions of TAE684 or DMSO for 2–3 days. Luciferase expression is used as a measure of cell proliferation/survival and is evaluated with the Bright-Glo Luciferase Assay System. IC50 values are generated by using XLFit software.
• Protocol: Animal Study ^[1]
• Animal Models: Karpas-299 xenografts are established in 4- to 6-week old female Fox Chase SCIDBeige mice.
• Formulation: Resuspended in 10% 1-methyl-2-pyrrolidinone/90% polyethylene glycol 300 solution
• Doses: 1, 3, and 10 mg/kg
• Administration: Once daily by oral gavage for 3 weeks

References

• References: [1] Galkin AV, et al. Proc Natl Acad Sci U S A, 2007, 104(1), 270-275.
• References: [2] Katayama R, et al. Proc Natl Acad Sci U S A, 2011, 108(18), 7535-7540.
• References: [3] Schönherr C, et al, Biochem J, 2011, 440(3), 405-413.

REFERENCES

• Galkin AV, et al. Proc Natl Acad Sci U S A, 2007, 104(1), 270-275.
• Katayama R, et al. Proc Natl Acad Sci U S A, 2011, 108(18), 7535-7540.
• Schönherr C, et al, Biochem J, 2011, 440(3), 405-413.