Taladegib (LY2940680) hydrochloride is a Smoothened ( SMO ) antagonist. Taladegib hydrochloride inhibits the Hedgehog signaling pathway, with an IC50 of 5.5 nM for suppressing GLI1 mRNA expression in DAOY cells and an IC50 of 7.6 nM in CGNP cell proliferation assays. Taladegib hydrochloride binds to the extracellular loop region (site 1) of the transmembrane domain of the SMO receptor, competes with cyclopamine for SMO binding, and thereby inhibits Gli -dependent transcription. Taladegib hydrochloride can be used in studies of Hedgehog pathway-related cancers [1] [2] [3] [4].
In Vivo, Taladegib (LY2940680) hydrochloride (100 μM; p.o.; daily; 5-7 days) reverses Aβ-induced immediate (3 min) and intermediate (1 h) memory impairment in a Drosophila Alzheimer's disease model[1]. Hydrochloride of Taladegib (1% (w/v); topical administration; single dose) potently inhibits Hedgehog pathway activity in the skin of depilated mice, reduces Gli1 mRNA by approximately 70%-80%, and results in low systemic plasma exposure[4].
In Vitro, Hydrochloride of Taladegib (LY2940680) (1-100 μM; 72 h) slightly inhibits the proliferation of primary cell cultures of mucinous-type IHCCA and mixed-type IHCCA, with IC50 values of 49.8 μM and 61.2 μM, respectively[2]. Taladegib hydrochloride potently inhibits SHH-induced GLI1 mRNA expression in human DAOY medulloblastoma cells, with a pIC50 of 8.26 and full efficacy[4]. Hydrochloride of Taladegib (20 μM; 72 h) does not induce apoptosis in primary cell cultures of mucinous IHCCA or mixed-type IHCCA[2]. Taladegib hydrochloride potently binds to wild-type human Smoothened, with a Ki value of 0.5 nM[3]. Taladegib hydrochloride exhibits significantly reduced binding affinity for the D473H mutant human Smoothened, with a Ki value of 55 nM[3]. Taladegib hydrochloride potently inhibits the constitutive activity of wild-type human SMO in CHO-K1 cell membranes, with a pIC50 of 6.53, and exhibits full inverse agonist efficacy[4]. Taladegib (LY2940680) hydrochloride potently inhibits the constitutive activity of the human SMOD473H mutant receptor on CHO-K1 cell membranes, with a pIC50 of 6.22, and exhibits full inverse agonist efficacy[4]. Taladegib hydrochloride inhibits the constitutive activity of the human SMOM2 (W535L) mutant receptor on CHO-K1 cell membranes, with a pIC50 of 5.75, and exhibits full inverse agonist potency[4]. Taladegib hydrochloride potently inhibits SHH-induced proliferation of rat CGNP cells, with a pIC50 of 8.12 and full efficacy[4].
References:
[1]. Ma W, et al. Reduced Smoothened level rescues Aβ-induced memory deficits and neuronal inflammation in animal models of Alzheimer's disease. Journal of genetics and genomics = Yi chuan xue bao. 2018 May 20;45(5):237-246.
[2]. Fraveto A, et al. Sensitivity of Human Intrahepatic Cholangiocarcinoma Subtypes to Chemotherapeutics and Molecular Targeted Agents: A Study on Primary Cell Cultures. PloS one. 2015;10(11):e0142124.
[3]. Hoch L, et al. MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptor. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2015 May;29(5):1817-29.
[4]. Lauressergues E, et al. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model. Pharmacology research & perspectives. 2016 Apr;4(2):e00214.
In Vivo, Taladegib (LY2940680) hydrochloride (100 μM; p.o.; daily; 5-7 days) reverses Aβ-induced immediate (3 min) and intermediate (1 h) memory impairment in a Drosophila Alzheimer's disease model[1]. Hydrochloride of Taladegib (1% (w/v); topical administration; single dose) potently inhibits Hedgehog pathway activity in the skin of depilated mice, reduces Gli1 mRNA by approximately 70%-80%, and results in low systemic plasma exposure[4].
In Vitro, Hydrochloride of Taladegib (LY2940680) (1-100 μM; 72 h) slightly inhibits the proliferation of primary cell cultures of mucinous-type IHCCA and mixed-type IHCCA, with IC50 values of 49.8 μM and 61.2 μM, respectively[2]. Taladegib hydrochloride potently inhibits SHH-induced GLI1 mRNA expression in human DAOY medulloblastoma cells, with a pIC50 of 8.26 and full efficacy[4]. Hydrochloride of Taladegib (20 μM; 72 h) does not induce apoptosis in primary cell cultures of mucinous IHCCA or mixed-type IHCCA[2]. Taladegib hydrochloride potently binds to wild-type human Smoothened, with a Ki value of 0.5 nM[3]. Taladegib hydrochloride exhibits significantly reduced binding affinity for the D473H mutant human Smoothened, with a Ki value of 55 nM[3]. Taladegib hydrochloride potently inhibits the constitutive activity of wild-type human SMO in CHO-K1 cell membranes, with a pIC50 of 6.53, and exhibits full inverse agonist efficacy[4]. Taladegib (LY2940680) hydrochloride potently inhibits the constitutive activity of the human SMOD473H mutant receptor on CHO-K1 cell membranes, with a pIC50 of 6.22, and exhibits full inverse agonist efficacy[4]. Taladegib hydrochloride inhibits the constitutive activity of the human SMOM2 (W535L) mutant receptor on CHO-K1 cell membranes, with a pIC50 of 5.75, and exhibits full inverse agonist potency[4]. Taladegib hydrochloride potently inhibits SHH-induced proliferation of rat CGNP cells, with a pIC50 of 8.12 and full efficacy[4].
References:
[1]. Ma W, et al. Reduced Smoothened level rescues Aβ-induced memory deficits and neuronal inflammation in animal models of Alzheimer's disease. Journal of genetics and genomics = Yi chuan xue bao. 2018 May 20;45(5):237-246.
[2]. Fraveto A, et al. Sensitivity of Human Intrahepatic Cholangiocarcinoma Subtypes to Chemotherapeutics and Molecular Targeted Agents: A Study on Primary Cell Cultures. PloS one. 2015;10(11):e0142124.
[3]. Hoch L, et al. MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptor. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2015 May;29(5):1817-29.
[4]. Lauressergues E, et al. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model. Pharmacology research & perspectives. 2016 Apr;4(2):e00214.