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Cat. No. Name Size Price Add Cart
KI0331GDC-044925 mg$88
GDC-044950 mg$160
GDC-0449100 mg$270
GDC-0449200 mg$440

Chemical Characteristic

Product NameGDC-0449
SynonymsVismodegib, HhAntag691
CAS No.879085-55-9
Molecular Weight 421.3
FormulaC19H14Cl2N2O3S
Chemical Name2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide
SmilesC(=O)(c1c(cc(cc1)S(=O)(=O)C)Cl)Nc1cc(c(cc1)Cl)c1ccccn1
Chemical Structure

Biological activities

GDC-0449 is a selective hedgehog (Hh) pathway inhibitor that blocks Hh signaling by binding to serpentine receptor Smoothened (SMO) and inhibiting activation of downstream Hh target genes.[1] In the Gli luciferase assay using human embryonic palatial mesenchyme (HEPM) cells, GDC-0449 possesses excellent potency with an IC50 of 13 nM.[2] GDC-0449 inhibits reporter activity at an IC50 of 20 nM in SMO-WT-transfected cells.[3] GDC-0449 acts as a potent inhibitor of smoothened and shows a high degree of selectivity for SHH-Gli signaling. Besides, GDC-0449 induces significant cell death in three pancreatic cancer cell lines (AsPC-1, PANC-1 and MIAPaCa-2) and pancreatic CSCs. In these cell lines, GDC-0449 induces apoptosis in a dose-dependent manner reaching up to 65%. In addition, GDC-0449 decreases SHH signaling components (Gli1, Gli2, Patched-1, Patched-2, SHH and Smoothened) expression, Gli-DNA binding and Gli luciferase reporter activities. Furthermore, GDC-0449 decreases the expression of PDGFRa concomitant with elevated levels of Fas, increases the expression of TRAIL-R1/DR4 and TRAIL-R2/DR5, decreases Bcl-2 expression, and induces caspase-3 activity and PARP cleavage. Exposure of CSCs with GDC-0449 for 36 hours results in inhibition of Gli-dependent luciferase reporter activity in a dose-dependent manner. [4] GDC-0449 (25 and 50 μM) inhibits concentration-dependent cell growth in HCC and H1339 cells. GDC-0449 also reduces side populations (SP) in HCC from 0.45 to 0.24% and in H1339 from 0.75 to 0.18%.[5] GDC-0449 has anti-tumor activity in a mouse model of medulloblastoma and in primary human tumor cell xenograft models, including colorectal cancer and pancreatic carcinoma correlated with blockade of the Hh pathway.[1] Meanwhile, GDC-0449 produces complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft moue model that is wholly dependent on the Hh pathway for growth. GDC-0449 shows excellent potency and low clearance in both rats and dogs.[2]

References

[1] LoRusso PM, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locallyadvanced or metastaticsolidtumors. Clin Cancer Res. 2011, 17(8): 2502-2511.
[2] Robarge KD, et al. GDC-0449?? potent inhibitor of the hedgehog pathway. Bioorg Med ChemLett. 2009, 19(19): 5576-5581.
[3] Yauch RL, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009, 326(5952): 572-574.
[4] Singh BN, et al. Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One. 2011, 6(11): e27306.
[5] Tian F, et al. Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations. Clin Exp Med. 2012, 12(1): 25-30.
[6] Dijkgraaf GJ, et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2011, 71(2): 435-444.

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