3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-8-methyl-3H,4H,7H,8H-pyrido[2,3-d]pyrimidine-4,7-dione

• ChemBase ID: 73117
• Molecular Formular: C17H15F2IN4O4
• Molecular Mass: 504.2266764
• Monoisotopic Mass: 504.01060942
• SMILES: n1(cnc2c(c1=O)c(c(c(=O)n2C)F)Nc1ccc(cc1F)I)C[C@@H](O)CO
• Canonical SMILES: OC[C@@H](Cn1cnc2c(c1=O)c(Nc1ccc(cc1F)I)c(c(=O)n2C)F)O
• InChI: InChI=1S/C17H15F2IN4O4/c1-23-15-12(16(27)24(7-21-15)5-9(26)6-25)14(13(19)17(23)28)22-11-3-2-8(20)4-10(11)18/h2-4,7,9,22,25-26H,5-6H2,1H3/t9-/m1/s1
• InChIKey: RCLQNICOARASSR-SECBINFHSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-8-methyl-3H,4H,7H,8H-pyrido[2,3-d]pyrimidine-4,7-dione
• IUPAC Traditional name: 3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-8-methylpyrido[2,3-d]pyrimidine-4,7-dione
• Synonyms: TAK733; TAK-733

Database IDs

• CAS Number: 1035555-63-5
• PubChem SID: 162038037
• PubChem CID: 24963252

CALCULATED PROPERTIES

• Acid pKa: 10.496048
• H Acceptors: 6
• H Donor: 3
• LogD (pH = 5.5): 0.3787669
• LogD (pH = 7.4): 0.37844202
• Log P: 0.37877268
• Molar Refractivity: 116.6259 cm^3
• Polarizability: 39.20156 Å^3
• Polar Surface Area: 105.47 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: false

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: MEK

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S2617

Research Area

• Description: Solid tumours

Biological Activity

• Description: TAK-733 is a potent, selective, non ATP-competitive MEK inhibitor with IC50 of 3.2 nM.
• Targets: MEK1/2
• IC50: 3.2 nM ^[1]
• In Vitro: TAK-733 is highly potent and selective MEK allosteric site inhibitor with IC50 of 3.2 nM. TAK-733 shows potent enzymatic and cell activity with an EC50 of 1.9 nM against ERK phosphorylation in cells. ^[1]
• In Vivo: TAK-733 demonstrates broad antitumor activity in mouse xenograft models of human cancer including models of melanoma, colorectal, NSCLC, pancreatic and breast cancer. TAK-733 is well tolerated with pharmacokinetics and pharmacodynamics that support once-daily oral dosing in humans. ^[1] TAK-733 shows maximally efficacious doses at once daily orally doses of 10 mg/kg. ^[2]
• Clinical Trials: A Multicenter, Open-label, Dose-escalation, Phase I Study of TAK-733, an Oral MEK Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies.

Combination Therapy

• Description: Alisertib at dose of 30 mg/kg combine with TAK-733 at dose of 10 mg/kg result in additive to synergistic antitumor activity and in prolonged inhibition of tumor regrowth in experimental human solid tumor xenograft models including NSCLC (NCI H23 [KRAS and LKB1 mutations]), CRC (SW620 [KRAS, APC, p53 mutations]), and pancreatic cancer (Panc 1 and Capan 1 [KRAS mutations] and BxPC-3 [No MAPK mutations]) models in immunocompromised mice. ^[2]

Protocol

• Protocol: Animal Study ^[2]
• Animal Models: Human solid tumor xenograft models including NSCLC (NCI H23 [KRAS and LKB1 mutations]), CRC (SW620 [KRAS, APC, p53 mutations]) Pancreatic cancer (Panc 1 and Capan 1 [KRAS mutations] and BxPC-3 [No MAPK mutations]) models in immunocompromised mice.
• Formulation: Saline
• Doses: 10 mg/kg
• Administration: Orally administrated once daily for 21 days

References

• References: [1] Qing Dong, et al. Bioorg Med Chem Lett, 2011, 21(5), 1315-1319.
• References: [2] Fabrey R, et al. AACR Annual Meeting, 2012, Abs 3739.

REFERENCES

• Qing Dong, et al. Bioorg Med Chem Lett, 2011, 21(5), 1315-1319.
• Fabrey R, et al. AACR Annual Meeting, 2012, Abs 3739.