GDC-0449

Catalog #:

IN0012

IN0012-5mg	USD150.0
IN0012-25mg	USD594.0

Synonyms: GDC-0449, Vismodegib

IUPAC Name:

2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

Functional Activity:

Vismodegib (GDC-0449) inhibits the Hedgehog (Hh) pathway, which is involved in tumorigenesis, thus providing a strong rationale for its use in the treatment of a variety of cancers. Vismodegib suppresses Hh signaling by binding to and interfering with smoothened, a membrane protein that provides positive signals to the Hh signaling pathway. Preclinical studies demonstrated the antitumor activity of vismodegib in mouse models of medulloblastoma (MB) and in xenograft models of colorectal and pancreatic cancer. Phase I clinical trials in patients with advanced basal cell carcinoma (BCC) and MB highlighted an objective response to vismodegib. Reported side effects were minor, with only one grade 4 adverse event. Vismodegib is currently undergoing phase II clinical trials for the treatment of advanced BCC, metastatic colorectal cancer, ovarian cancer, MB and other solid tumors. Because of its low toxicity and specificity for the Hh pathway, this drug has potential advantages compared with conventional chemotherapy, and may also be used in combination treatments. Clinical trials with other Hh inhibitors are also ongoing and their therapeutic potential will need to be compared with vismodegib.

Technical Data:

M.Wt: 421.3

Formula: C₁₉H₁₄ Cl₂ N₂O₃S

Solubility: DMSO

Purity: >99%

Storage: Dessicate at -20 degree C for 2 years

CAS No.: 879085-55-9

Related Products by Target:

Cyclopamine

References for GDC-0449:

1. LoRusso, P. M., Rudin, C. M., Reddy, J. C., Tibes, R., Weiss, G. J., Borad, M. J., Hann, C. L., Brahmer, J. R., Chang, I., Darbonne, W. C., Graham, R. A., Zerivitz, K. L., Low, J. A., and Von Hoff, D. D. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res, 17: 2502-2511.

2. Graham, R. A., Lum, B. L., Cheeti, S., Jin, J. Y., Jorga, K., Von Hoff, D. D., Rudin, C. M., Reddy, J. C., Low, J. A., and Lorusso, P. M. Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. Clin Cancer Res, 17: 2512-2520.

3. Dijkgraaf, G. J., Alicke, B., Weinmann, L., Januario, T., West, K., Modrusan, Z., Burdick, D., Goldsmith, R., Robarge, K., Sutherlin, D., Scales, S. J., Gould, S. E., Yauch, R. L., and de Sauvage, F. J. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res, 71: 435-444.

4. Amin, S. H., Tibes, R., Kim, J. E., and Hybarger, C. P. Hedgehog antagonist GDC-0449 is effective in the treatment of advanced basal cell carcinoma. Laryngoscope, 120: 2456-2459.

5. Wong, H., Theil, F. P., Cui, Y., Marsters, J. C., Jr., Khojasteh, S. C., Vernillet, L., La, H., Song, X., Wang, H., Morinello, E. J., Deng, Y., and Hop, C. E. Interplay of dissolution, solubility, and nonsink permeation determines the oral absorption of the Hedgehog pathway inhibitor GDC-0449 in dogs: an investigation using preclinical studies and physiologically based pharmacokinetic modeling. Drug Metab Dispos, 38: 1029-1038.

6. Ding, X., Chou, B., Graham, R. A., Cheeti, S., Percey, S., Matassa, L. C., Reuschel, S. A., Meng, M., Liu, S., Voelker, T., Lum, B. L., Rudewicz, P. J., and Hop, C. E. Determination of GDC-0449, a small-molecule inhibitor of the Hedgehog signaling pathway, in human plasma by solid phase extraction-liquid chromatographic-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci, 878: 785-790.

7. Doggrell, S. A. The hedgehog pathway inhibitor GDC-0449 shows potential in skin and other cancers. Expert Opin Investig Drugs, 19: 451-454.

8. Dierks, C. GDC-0449--targeting the hedgehog signaling pathway. Recent Results Cancer Res, 184: 235-238.

9. Wong, H., Chen, J. Z., Chou, B., Halladay, J. S., Kenny, J. R., La, H., Marsters, J. C., Jr., Plise, E., Rudewicz, P. J., Robarge, K., Shin, Y., Wong, S., Zhang, C., and Khojasteh, S. C. Preclinical assessment of the absorption, distribution, metabolism and excretion of GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide) , an orally bioavailable systemic Hedgehog signalling pathway inhibitor. Xenobiotica, 39: 850-861, 2009.

10. Rudin, C. M., Hann, C. L., Laterra, J., Yauch, R. L., Callahan, C. A., Fu, L., Holcomb, T., Stinson, J., Gould, S. E., Coleman, B., LoRusso, P. M., Von Hoff, D. D., de Sauvage, F. J., and Low, J. A. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med, 361: 1173-1178, 2009.

11. Robarge, K. D., Brunton, S. A., Castanedo, G. M., Cui, Y., Dina, M. S., Goldsmith, R., Gould, S. E., Guichert, O., Gunzner, J. L., Halladay, J., Jia, W., Khojasteh, C., Koehler, M. F., Kotkow, K., La, H., Lalonde, R. L., Lau, K., Lee, L., Marshall, D., Marsters, J. C., Jr., Murray, L. J., Qian, C., Rubin, L. L., Salphati, L., Stanley, M. S., Stibbard, J. H., Sutherlin, D. P., Ubhayaker, S., Wang, S., Wong, S., and Xie, M. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg Med Chem Lett, 19: 5576-5581, 2009.

Certificate of Analysis/MSDS is available upon request with lot number