SAG is a small molecule Hedgehog (Hh) pathway agonist with EC50 of 3 nM, specifically binds to the Smoothened (Smo) heptahelical bundle (Kd=59 nM); effectively activates Shh target gene transcription through the Smoothened (Smo) protein, acts downstream of Ptch1 in the Hh pathway and counteracts cyclopamine inhibition of Smo; increases Cldn5 expression, decreases endoneurial capillary permeability, and restores thermal algesia to diabetic mice; SAG inhibits melanin synthesis in melanocytes and pigmentation in a human skin model.

A potent, selective, orally bioavailable smoothened (Smo) inhibitor, blocks Shh signaling with EC50 of 40 nM; inhibits proliferation, increases apoptosis, and alters morphology, suppresses the Shh pathway in mouse medulloblastoma in vivo; also is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp; The first Hedgehog signaling pathway targeting agent to gain FDA approval.

Smoothib is a novel potent inhibitor of hedgehog (Hh) signaling (IC50=157¡À118 nM) and an antagonist of the protein smoothened (Smo), binds to the heptahelical bundle of Smo with Kd of 59 nM; inhibits Gli-mediated luciferase expression with IC50 of 1.4 uM in Gli-dependent reporter gene assay, reduces the expression of Hh target genes, and suppresses the growth of Ptch+/- medulloblastoma cells.

Saridegib (Patidegib, IPI-926) is a potent and orally active Hedgehog (Hh) pathway antagonist with IC50 of 7 nM; binds to and inhibits the cell membrane-spanning G-protein coupled receptor SMO; demonstrates improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and IPI-269609; completely suppresses tumor growth in a Hh-dependent medulloblastoma allograft model.

SANT-1 is a potent, cell-permeable Smoothened inhibitor (Kd=1.2 nM) that inhibits Sonic hedgehog (Shh) signaling; inhibits smoothened agonist effects with an IC50 of 20 nM in Shh-LIGHT2 cells; significantly reduces Gli1 gene expression, and reduces proliferation of glioma stem-like cells.

SAG is a small molecule Hedgehog (Hh) pathway agonist with EC50 of 3 nM, specifically binds to the Smoothened (Smo) heptahelical bundle (Kd=59 nM); effectively activates Shh target gene transcription through the Smoothened (Smo) protein, acts downstream of Ptch1 in the Hh pathway and counteracts cyclopamine inhibition of Smo; increases Cldn5 expression, decreases endoneurial capillary permeability, and restores thermal algesia to diabetic mice; SAG inhibits melanin synthesis in melanocytes and pigmentation in a human skin model.

MU1300 (MU-1300) is novel effective, selective modulator of the Hedgehog (Hh) pathway, suppresses Hh-dependent osteogenesis with IC50 of 300 nM in osteoblast differentiation assay using C3H10T1/2 cells, targets and binds to Smoothened (Smo) directly; MU1300 inhibited the GLI-mediated response with IC50 of 400 nM in GLI-dependent reporter gene assay using Shh-LIGHT2 cells; reduces the expression of the Hh target genes Gli1 and Ptch1 by 55% and 63% in NIH-3T3 cells in RT-qPCR analysis; Only inhibits only 5 kinases to 40-60% at 10 uM in Thermo Fisher SelectScreen kinase panel (454 kinases).

MRT-83 hydrochloride is a potent Smoothened antagonist that blocks Hedgehog (Hh) signaling in various assays with IC50 of 10 nM; inhibits Bodipy-cyclopamine binding to human and mouse Smo but does not modify Wnt signaling, blocks BC binding to HEK-hSmo cells with IC50 of 4.6 nM; abrogates the agonist-induced trafficking of endogenous mouse or human Smo, efficiently antagonizes Hh signaling in vivo.

MRT-83 is a potent Smoothened antagonist that blocks Hedgehog (Hh) signaling in various assays with IC50 of 10 nM; inhibits Bodipy-cyclopamine binding to human and mouse Smo but does not modify Wnt signaling, blocks BC binding to HEK-hSmo cells with IC50 of 4.6 nM; abrogates the agonist-induced trafficking of endogenous mouse or human Smo, efficiently antagonizes Hh signaling in vivo.

A novel potent, orally bioavailable and brain penetrating Hedgehog pathway (Hh) inhibitor that inhibits Smoothened (Smo) with IC50 of 1.1 uM; inhibits Hh signaling in a reporter gene assay in cancer cells with IC50 of 1-1.5 uM, also inhibited the proliferation of medulloblastoma cells derived from neonatally irradiated Ptch1−/+ mice in vitro with IC50 of 0.3 uM; demonstrate a robust antitumor activity against Hh-driven tumors in vivo, shows potentiation for the treatment of medulloblastoma and BCC.