TAK-441

TAK-441 is a highly potent and orally active hedgehog (Hh) signaling inhibitor with an IC₅₀value of 4.4 nM. TAK-441 has strong antitumor activity in solid tumors^[1][2][3]. IC50 & Target: IC50: 4.4 nM (Gli-luc reporter)^[1] In Vitro: 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^[1].
TAK-441 (0.03–1000 nM, 48 h) inhibits Gli1 mRNA with IC₅₀ values of 0.0457 and 0.113 mg/ml in the tumor and skin, respectively^[1].
TAK-441 (0.5-500 nM, 48-72 h) does not affect androgen withdrawal-induced Shh up-regulation or viability of LNCaP cells^[3].
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^[3]. In Vivo: TAK-441 (compound 11d) (oral; 10 mg/kg, 100 mg/kg) has favorable exposure and good oral absorption in BALB/c-nu/nu mice^[1].
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^[1].
TAK-441 (iv, 1 mg/kg; po, 10 mg/kg) is able to achieve sufficient exposure following oral administration in rats and dogs^[1].
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^[1].
Pharmacokinetic Parameters of TAK-441 in BALB/c-nu/nu mice (oral and Alzet infusion administration; 100 mg/kg; single)^[1].

Compd			Mouse PK 10mg/kg				Mouse PK 100mg/kg
		Cmax (lg/mL)		AUC (lgh/mL)		Cmax (lg/mL)		AUC (lgh/mL)
1		2.65		12.1		3.63		32.3
11d		5.62		28.3		21.5		206