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Vismodegib

Description of Vismodegib: Vismodegib (formerly GDC-0449)  is a hedgehog antagonist, is also an orally bioavailable small molecule with potential antineoplastic activity. Hedgehog antagonist GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. The Hedgehog signaling pathway plays an important role in tissue growth and repair; aberrant constitutive activation of Hedgehog pathway signaling and uncontrolled cellular proliferation may be associated with mutations in the Hedgehog-ligand cell surface receptors PTCH and SMO. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Vismodegib (GDC-0449) is a small, orally administrable molecule, belonging to the 2-arylpyridine class, which was discovered by Genentech Inc under a collaboration with Curis Inc. Vismodegib 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. (source: Curr Opin Investig Drugs. 2010 Jun;11(6):707-18. or http://www.ncbi.nlm.nih.gov/pubmed/20496266).

When it became apparent that aberrant hedgehog (HH) pathway signaling was a likely mediator in the development of tumors, especially basal cell carcinoma, many companies began to investigate the use of small-molecule inhibitors of key steps in the HH pathway as potential anticancer agents. Under normal physiological conditions the pathway controls embryonic development via HH ligand binding to the patched (PTC) receptor, which inhibits a second receptor, smoothened (SMO), which in turn regulates glioma-associated oncogene (GLI)-mediated transcription of pro- and antiapoptotic genes. Genentech and Curis developed vismodegib (GDC-0449), a small-molecule inhibitor of SMO, which was proven to be the first such compound to successfully target tumorigenesis in humans. In preclinical pharmacokinetic and pharmacodynamic studies, vismodegib demonstrated promising characteristics for use in humans, more so than its predecessor Hh-Antag691. Vismodegib successfully entered phase I clinical trials in patients with basal cell carcinoma and medulloblastoma, and is currently under investigation in a number of phase II trials for various cancers, including basal cell carcinoma, medulloblastoma, pancreatic, ovarian, stomach and breast cancers, in addition to a number of phase II trials investigating its use in combination with other chemotherapeutic agents such as bevacizumab. (source: Haddley, K. Drugs Fut 2010, 35(5): 379, or http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=1500428&p_IsPs=N).

Current developer:    Genentech/Curis

1: Tian F, Schrödl K, Kiefl R, Huber RM, Bergner A. The Hedgehog Pathway Inhibitor GDC-0449 Alters Intracellular Ca2+ Homeostasis and Inhibits Cell Growth in Cisplatin-resistant Lung Cancer Cells. Anticancer Res. 2012 Jan;32(1):89-94. PubMed PMID: 22213292.

2: Singh BN, Fu J, Srivastava RK, Shankar S. Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One. 2011;6(11):e27306. Epub 2011 Nov 8. PubMed PMID: 22087285; PubMed Central PMCID: PMC3210776.

3: Lorusso PM, Jimeno A, Dy G, Adjei A, Berlin J, Leichman L, Low JA, Colburn D, Chang I, Cheeti S, Jin JY, Graham RA. Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors. Clin Cancer Res. 2011 Sep 1;17(17):5774-82. Epub 2011 Jul 13. PubMed PMID: 21753154.

4: Deng Y, Wong H, Graham RA, Liu W, Shen HS, Shi Y, Wang L, Meng M, Malhi V, Ding X, Dean B. Determination of unbound vismodegib (GDC-0449) concentration in human plasma using rapid equilibrium dialysis followed by solid phase extraction and high-performance liquid chromatography coupled to mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Jul 15;879(22):2119-26. Epub 2011 Jun 12. PubMed PMID: 21704573.

5: Graham RA, Lum BL, Morrison G, Chang I, Jorga K, Dean B, Shin YG, Yue Q, Mulder T, Malhi V, Xie M, Low JA, Hop CE. A single dose mass balance study of the Hedgehog pathway inhibitor vismodegib (GDC-0449) in humans using accelerator mass spectrometry. Drug Metab Dispos. 2011 Aug;39(8):1460-7. Epub 2011 May 20. PubMed PMID: 21602311.

6: Tian F, Mysliwietz J, Ellwart J, Gamarra F, Huber RM, Bergner A. Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations. Clin Exp Med. 2011 Apr 26. [Epub ahead of print] PubMed PMID: 21519961.

7: Giannetti AM, Wong H, Dijkgraaf GJ, Dueber EC, Ortwine DF, Bravo BJ, Gould SE, Plise EG, Lum BL, Malhi V, Graham RA. Identification, characterization, and implications of species-dependent plasma protein binding for the oral Hedgehog pathway inhibitor vismodegib (GDC-0449). J Med Chem. 2011 Apr 28;54(8):2592-601. Epub 2011 Mar 25. PubMed PMID: 21438527.

8: Goldberg LH, Landau JM, Moody MN, Kazakevich N, Holzer AM, Myers A. Resolution of odontogenic keratocysts of the jaw in basal cell nevus syndrome with GDC-0449. Arch Dermatol. 2011 Jul;147(7):839-41. Epub 2011 Mar 21. PubMed PMID: 21422324.

9: Yue Q, Chen YH, Mulder T, Deese A, Takahashi R, Rudewicz PJ, Reynolds M, Solon E, Hop CE, Wong H, Khojasteh SC. Absorption, distribution, metabolism, and excretion of [¹⁴C]GDC-0449 (vismodegib), an orally active hedgehog pathway inhibitor, in rats and dogs: a unique metabolic pathway via pyridine ring opening. Drug Metab Dispos. 2011 Jun;39(6):952-65. Epub 2011 Mar 1. PubMed PMID: 21363998.

10: LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Chang I, Darbonne WC, Graham RA, Zerivitz KL, Low JA, Von Hoff DD. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011 Apr 15;17(8):2502-11. Epub 2011 Feb 7. PubMed PMID: 21300762.

11: Graham RA, Lum BL, Cheeti S, Jin JY, Jorga K, Von Hoff DD, Rudin CM, Reddy JC, Low JA, Lorusso PM. 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. 2011 Apr 15;17(8):2512-20. Epub 2011 Feb 7. PubMed PMID: 21300760.

12: Dijkgraaf GJ, Alicke B, Weinmann L, Januario T, West K, Modrusan Z, Burdick D, Goldsmith R, Robarge K, Sutherlin D, Scales SJ, Gould SE, Yauch RL, de Sauvage FJ. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2011 Jan 15;71(2):435-44. Epub 2010 Dec 1. PubMed PMID: 21123452.

13: Amin SH, Tibes R, Kim JE, Hybarger CP. Hedgehog antagonist GDC-0449 is effective in the treatment of advanced basal cell carcinoma. Laryngoscope. 2010 Dec;120(12):2456-9. doi: 10.1002/lary.21145. PubMed PMID: 20927781.

14: Wong H, Theil FP, Cui Y, Marsters JC Jr, Khojasteh SC, Vernillet L, La H, Song X, Wang H, Morinello EJ, Deng Y, Hop CE. 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. 2010 Jul;38(7):1029-38. Epub 2010 Apr 20. PubMed PMID: 20406853.

15: Ding X, Chou B, Graham RA, Cheeti S, Percey S, Matassa LC, Reuschel SA, Meng M, Liu S, Voelker T, Lum BL, Rudewicz PJ, Hop CE. 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. 2010 Mar 15;878(9-10):785-90. Epub 2010 Feb 1. PubMed PMID: 20172765.

16: Doggrell SA. The hedgehog pathway inhibitor GDC-0449 shows potential in skin and other cancers. Expert Opin Investig Drugs. 2010 Mar;19(3):451-4. PubMed PMID: 20078247.

17: Dierks C. GDC-0449--targeting the hedgehog signaling pathway. Recent Results Cancer Res. 2010;184:235-8. Review. PubMed PMID: 20072843.

18: Wong H, Chen JZ, Chou B, Halladay JS, Kenny JR, La H, Marsters JC Jr, Plise E, Rudewicz PJ, Robarge K, Shin Y, Wong S, Zhang C, Khojasteh SC. 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. 2009 Nov;39(11):850-61. PubMed PMID: 19845436.

19: Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B, LoRusso PM, Von Hoff DD, de Sauvage FJ, Low JA. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009 Sep 17;361(12):1173-8. Epub 2009 Sep 2. PubMed PMID: 19726761.

20: Robarge KD, Brunton SA, Castanedo GM, Cui Y, Dina MS, Goldsmith R, Gould SE, Guichert O, Gunzner JL, Halladay J, Jia W, Khojasteh C, Koehler MF, Kotkow K, La H, Lalonde RL, Lau K, Lee L, Marshall D, Marsters JC Jr, Murray LJ, Qian C, Rubin LL, Salphati L, Stanley MS, Stibbard JH, Sutherlin DP, Ubhayaker S, Wang S, Wong S, Xie M. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5576-81. Epub 2009 Aug 15. Erratum in: Bioorg Med Chem Lett. 2010 Jan 15;20(2):771. PubMed PMID: 19716296.