TAK-441

Research use only, not for human use.

TAK-441 is an orally active inhibitor of Hedgehog signaling(IC50 = 4.4 nM) with potent antitumor activity. TAK-441 suppresses transcription factor Gli1 mRNA expression and tumor growth.

TAK-441 is a highly potent and orally active hedgehog (Hh) signaling inhibitorwith an IC50value of 4.4 nM. TAK-441 has strong antitumor activity in solid tumors.

TAK-441 (compound 11d) (0.03–1000 nM, 48 h) has potent activity in the Gli-luc reporter with an IC50 value of 4.4 nM and good solubility. TAK-441 (0.03–1000 nM, 48 h) inhibits Gli1 mRNA with IC50 values of 0.0457 and 0.113 mg/mlin the tumor and skin, respectively. TAK-441 (0.5-500 nM, 48-72 h) does not affect androgen withdrawal-induced Shh up-regulation or viability of LNCaP cells. TAK-441 (0.5-500 nM, 48-72 h) leads to delayed castration-resistant progression of LNCaP xenografts by disrupting paracrine Hh signaling with the tumor stroma.Cell Viability Assay Cell Line:NIH3T3/Gli-luc cells Concentration:0.03–1000 nM Incubation Time:48 h Result:Showed acceptable solubility and potent Hh inhibitory activity.Cell Cytotoxicity Assay Cell Line:LNCaP cells Concentration:0.5-500 nMIncubation Time:48-72 h Result:Did not affect up-regulation of Shh of in vitro viability of LNCaP cells under androgen-deprivedconditionsin.Western Blot Analysis Cell Line:LNCaP, C4-2, DU145 and PC3 cells Concentration: Incubation Time:Result:Reflected androgen-responsive PCa and express both Shh and Dhh in LNCaP and C4-2 cells and reflect restricted Shh expression of CRPC in DU145 and PC3 cells.

TAK-441 (compound 11d) (oral; 10 mg/kg, 100 mg/kg) has favorable exposure and good oral absorption in BALB/c-nu/nu mice.TAK-441 (oral, 1 and 25 mg/kg, QD for 14 days) has strong antitumor activity and can achieve dose-dependent plasma and tumor concentrations by improving the solubility of TAK-441 in Ptc1+/-p53-/- mice bearing medulloblastoma allografts.TAK-441 (iv, 1 mg/kg; po, 10 mg/kg) is able to achieve sufficient exposure following oral administration in rats and dogs.TAK-441 (oral; 1, 10, and 25 mg/kg) shows dose-dependent antitumor activity in xenografted mice, the IC50 value for the tumor growth inhibition is 0.075 mg/ml. Pharmacokinetic Parameters of TAK-441 in BALB/c-nu/nu mice (oral and Alzet infusion administration; 100 mg/kg; single).Animal Model:BALB/c-nu/nu mice Dosage:10 mg/kg, 100 mg/kg Administration:oral; 10 mg/kg, 100 mg/kg Result:Inhibits Gli1 mRNA in the tumor and skin with IC50 values of 0.0457 mg/mL and 0.113 mg/mL, respectively.Animal Model: Ptc1+/-p53-/- mice Dosage:1 and 25 mg/kg Administration:oral, 1 and 25 mg/kg, QD for 14 days Result:Showed strong antitumor activity and resulted in a dose-dependent PK profile by improving solubility.

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GPCR/G Protein

Hedgehog (Hh)

Hedgehog/Smoothened

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1186231-83-3

576.56

C28H31F3N4O6

>98% (HPLC)

In Vitro:?DMSO : 100 mg/mL (173.44 mM; Ultrasonic )

O(CC(F)(F)F)C=1C2=C(N(C)C1C(NC3CCN(C(CO)=O)CC3)=O)C=C(CC)N(CC(=O)C4=CC=CC=C4)C2=O

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(-20℃)

With Ice Pack

≥ 2 years