1,274
Views
47
CrossRef citations to date
0
Altmetric
Drug Discovery Case History

Discovery and preclinical development of vismodegib

, PhD, , MD PhD, , PhD, , PhD, , PhD, , PhD, , PhD, , PhD & , PhD show all

Bibliography

  • Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980;287:795-801
  • Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001;15:3059-87
  • Wang Y, McMahon AP, Allen BL. Shifting paradigms in Hedgehog signaling. Curr Opin Cell Biol 2007;19:159-65
  • Miura H, Kusakabe Y, Sugiyama C, et al. Shh and Ptc are associated with taste bud maintenance in the adult mouse. Mech Dev 2001;106:143-5
  • Wang LC, Liu ZY, Gambardella L, et al. Regular articles: conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration. J Invest Dermatol 2000;114:901-8
  • Seidel K, Ahn CP, Lyons D, et al. Hedgehog signaling regulates the generation of ameloblast progenitors in the continuously growing mouse incisor. Development 2010;137:3753-61
  • Bitgood MJ, Shen L, McMahon AP. Sertoli cell signaling by desert hedgehog regulates the male germline. Curr Biol 1996;6:298-304
  • Clark AM, Garland KK, Russell LD. Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules. Biol Reprod 2000;63:1825-38
  • Maeda Y, Nakamura E, Nguyen MT, et al. Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone. Proc Natl Acad Sci USA 2007;104:6382-7
  • St-Jacques B, Hammerschmidt M, McMahon AP. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 1999;13:2072-86
  • Mar BG, Amakye D, Aifantis I, Buonamici S. The controversial role of the Hedgehog pathway in normal and malignant hematopoiesis. Leukemia 2011;25:1665-73
  • Hofmann I, Stover EH, Cullen DE, et al. Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell 2009;4:559-67
  • Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev 2008;22:2454-72
  • Ingham PW, Placzek M. Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet 2006;7:841-50
  • Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 2006;5:1026-33
  • Huangfu D, Anderson KV. Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 2006;133:3-14
  • Stone DM, Hynes M, Armanini M, et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic Hedgehog. Nature 1996;384:129-34
  • Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of Smoothened. Nature 2002;418:892-7
  • Nedelcu D, Liu J, Xu Y, et al. Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling. Nat Chem Biol 2013;9:557-64
  • Sharpe HJ, de Sauvage FJ. Signaling: an oxysterol ligand for Smoothened. Nat Chem Biol 2012;8:139-40
  • Pentchev PG, Brady RO, Blanchette-Mackie EJ, et al. The Niemann-Pick C lesion and its relationship to the intracellular distribution and utilization of LDL cholesterol. Biochim Biophys Acta 1994;1225:235-43
  • Robbins DJ, Fei DL, Riobo NA. The Hedgehog signal transduction network. Sci Signal 2012;5:re6
  • Ruiz i Altaba A. Catching a Gli-mpse of Hedgehog. Cell 1997;90:193-6
  • Chen Y, Gallaher N, Goodman RH, Smolik SM. Protein kinase A directly regulates the activity and proteolysis of cubitus interruptus. Proc Natl Acad Sci USA 1998;95:2349-54
  • Price MA, Kalderon D. Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by protein kinase A. Development 1999;126:4331-9
  • Price MA, Kalderon D. Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell 2002;108:823-35
  • Jia J, Amanai K, Wang G, et al. Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature 2002;416:548-52
  • Pan Y, Bai CB, Joyner AL, Wang B. Sonic Hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol 2006;26:3365-77
  • Yoon JW, Kita Y, Frank DJ, et al. Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem 2002;277:5548-55
  • Ruiz i AA, Sanchez P, Dahmane N. Gli and Hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2002;2:361-72
  • Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996;272:1668-71
  • Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996;85:841-51
  • Teh M-T, Blaydon D, Chaplin T, et al. Genomewide single nucleotide polymorphism microarray mapping in basal cell carcinomas unveils uniparental disomy as a key somatic event. Cancer Res 2005;65:8597-603
  • Danaee H, Karagas MR, Kelsey KT, et al. Allelic loss at Drosophila patched gene is highly prevalent in Basal and squamous cell carcinomas of the skin. J Invest Dermatol 2006;126:1152-8
  • Xie J, Murone M, Luoh SM, et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 1998;391:90-2
  • Reifenberger J, Wolter M, Knobbe CB, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 2005;152:43-51
  • Dahmane N, Lee J, Robins P, et al. Activation of the transcription factor Gli1 and the Sonic Hedgehog signalling pathway in skin tumours. Nature 1997;389:876-81
  • Green J, Leigh IM, Poulsom R, Quinn AG. Basal cell carcinoma development is associated with induction of the expression of the transcription factor Gli-1. Br J Dermatol 1998;139:911-15
  • Unden AB, Zaphiropoulos PG, Bruce K, et al. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res 1997;57:2336-40
  • Gailani MR, Stahle-Backdahl M, Leffell DJ, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 1996;14:78-81
  • Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore) 1987;66:98-113
  • Gorlin RJ. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med 2004;6:530-9
  • Goussia AC, Bruner JM, Kyritsis AP, et al. Cytogenetic and molecular genetic abnormalities in primitive neuroectodermal tumors of the central nervous system. Anticancer Res 2000;20:65-73
  • Corcoran RB, Scott MP. A mouse model for medulloblastoma and basal cell nevus syndrome. J Neurooncol 2001;53:307-18
  • Kool M, Korshunov A, Remke M, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 2012;123:473-84
  • Northcott PA, Jones DT, Kool M, et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer 2012;12:818-34
  • Romer JT, Kimura H, Magdaleno S, et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice. Cancer Cell 2004;6:229-40
  • Tang T, Tang JY, Li D, et al. Targeting superficial or nodular Basal cell carcinoma with topically formulated small molecule inhibitor of smoothened. Clin Cancer Res 2011;17:3378-87
  • Incardona JP, Gaffield W, Kapur RP, Roelink H. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic Hedgehog signal transduction. Development 1998;125:3553-62
  • Heretsch P, Tzagkaroulaki L, Giannis A. Cyclopamine and Hedgehog signaling: chemistry, biology, medical perspectives. Angew Chem Int Ed Engl 2010;49:3418-27
  • Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002;16:2743-8
  • Dellovade T, Romer JT, Curran T, Rubin LL. The Hedgehog pathway and neurological disorders. Annu Rev Neuro 2006;29:539-63
  • Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003;425:846-51
  • Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004;431:707-12
  • Thayer SP, di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003;425:851-6
  • Watkins DN, Berman DM, Burkholder SG, et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003;422:313-17
  • Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for Hedgehog signalling in cancer. Nature 2008;455:406-10
  • Brunton SA, Stibbard JH, Rubin LL, et al. Potent inhibitors of the Hedgehog signaling pathway. J Med Chem 2008;51:1108-10
  • Frank-Kamenetsky M, Zhang XM, Bottega S, et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol 2002;1:10
  • Williams JA, Guicherit OM, Zaharian BI, et al. Identification of a small molecule inhibitor of the Hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci USA 2003;100:4616-21
  • Chen JK, Taipale J, Young KE, et al. Small molecule modulation of Smoothened activity. Proc Natl Acad Sci USA 2002;99:14071-6
  • Dijkgraaf GJ, Alicke B, Weinmann L, et al. Small molecule inhibition of GDC-0449 refractory Smoothened mutants and downstream mechanisms of drug resistance. Cancer Res 2011;71:435-44
  • Robarge KD, Brunton SA, Castanedo GM, et al. GDC-0449-a potent inhibitor of the Hedgehog pathway. Bioorg Med Chem Lett 2009;19:5576-81
  • In a survey of the Cambridge Structural Database, the torsion profile between amides and aryl rings peak at angles around 30° and 150° for unsubstituted benzamides whereas this distribution peaks at angles of around 60° and 120° for ortho-chloro benzamides
  • Zhang Y, Laterra J, Pomper MG. Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp. Neoplasia 2009;11:96-101
  • Wong H, Choo EF, Alicke B, et al. Antitumor activity of targeted and cytotoxic agents in murine subcutaneous tumor models correlates with clinical response. Clin Cancer Res 2012;18:3846-55
  • Yauch RL, Dijkgraaf GJ, Alicke B, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 2009;326:572-4
  • Wong H, Alicke B, West KA, et al. Pharmacokinetic-pharmacodynamic analysis of vismodegib in preclinical models of mutational and ligand-dependent Hedgehog pathway activation. Clin Cancer Res 2011;17:4682-92
  • Wong H, Chen JZ, Chou B, et al. 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;39:850-61
  • Giannetti AM, Wong H, Dijkgraaf GJ, et al. Identification, characterization, and implications of species-dependent plasma protein binding for the oral Hedgehog pathway inhibitor vismodegib (GDC-0449). J Med Chem 2011;54:2592-601
  • Yue Q, Chen YH, Mulder T, et al. 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;39:952-65
  • Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res 1993;10:1093-5
  • Wong H, Theil FP, Cui Y, et al. 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 Metabol Dispos 2010;38:1029-38
  • Lin JH. Applications and limitations of interspecies scaling and in vitro extrapolation in pharmacokinetics. Drug Metab Dispos 1998;26:1202-12
  • LoRusso PM, Rudin CM, Reddy JC, et al. Phase I trial of Hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res 2011;17:2502-11
  • Graham RA, Hop CE, Borin MT, et al. Single and multiple dose intravenous and oral pharmacokinetics of the Hedgehog pathway inhibitor vismodegib in healthy female subjects. Br J Clin Pharmacol 2012;74:788-96
  • Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with Hedgehog pathway inhibitor GDC-0449. New Eng J Med 2009;361:1173-8
  • Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the Hedgehog pathway in advanced basal-cell carcinoma. New Eng J Med 2009;361:1164-72
  • Bossi P, Perrone F, Cortellazzi B, et al. Abstract PR05: resistance to Hedgehog inhibitor through Smoothened receptor mutation in basal cell carcinoma. Mol Can Ther 2013;12(11 Suppl):PR05
  • Ding X, Chou B, Graham RA, et al. 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;878:785-90
  • Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. New Eng J Med 2012;366:2171-9
  • Berlin J, Bendell JC, Hart LL, et al. A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin Cancer Res 2013;19:258-67
  • Kaye SB, Fehrenbacher L, Holloway R, et al. A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission. Clin Cancer Res 2012;18:6509-18
  • Hadden MK. Hedgehog pathway inhibitors: a patent review (2009--present). Expert Opin Ther Pat 2013;23:345-61
  • ClinicalTrials.gov Identifier NCT00953758. A Study of PF-04449913 in Select Hematologic Malignancies. Available from: http://clinicaltrials.gov/ct2/show/NCT00953758?term=NCT00953758&rank=1
  • ClinicalTrials.gov Identifier NCT01286467. A Study of PF-04449913 Administered Alone in Select Solid Tumors. Available from: http://clinicaltrials.gov/ct2/show/NCT01286467?term=NCT01286467&rank=1
  • Levin WJ. Cycling toward leukemia stem cell elimination with a selective sonic Hedgehog antagonist. Presented at: 20th Molecular Medicine Tri-Conference; 11 – 15 February 2013; San Francisco, CA
  • Rodon J, Tawbi HA, Thomas AL, et al. Phase I study of the Smoothened (SMO) antagonist LDE225 in patients with advanced solid tumors: preliminary safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity in medulloblastoma [abstract OT-12]. Presented at: 16th Annual Scientific Meeting of the Society of Neuro-Oncology; 17 – 20 November 2011; Garden Grove, CA
  • Bender MH, Hipskind PA, Capen AR, et al. Identification and characterization of a novel Smoothened antagonist for the treatment of cancer with deregulated Hedgehog signaling Presented at: 102nd Annual Meeting of the AACR; Orlando, FL. Abstract 2819. Cancer Res 2011. 71(8 Suppl):2819
  • ClinicalTrials.gov Identifier NCT01226485. A Study in Advanced Cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT01226485?term=NCT01226485&rank=1
  • ClinicalTrials.gov Identifier NCT01204073. A Study of TAK-441 in Adult Patients With Advanced Nonhematologic Malignancies. Available from: http://clinicaltrials.gov/ct2/show/NCT01204073?term=NCT01204073&rank=1
  • Goldman JW, Eckhardt SG, Borad M, et al. Phase 1 dose-escalation trial of the investigational Hedgehog (HH) pathway inhibitor TAK-441 in patients with advanced solid tumors. Ann Oncol 2012;23:152-74
  • ClinicalTrials.gov Identifier NCT01310816. A Safety and Efficacy Study of Patients With Metastatic or Locally Advanced (Unresectable) Chondrosarcoma. Available from: http://clinicaltrials.gov/ct2/show/NCT01310816?term=NCT01310816&rank=1
  • ClinicalTrials.gov Identifier NCT01371617. A Phase 2 Study With IPI-926 in Patients With Myelofibrosis. Available from: http://clinicaltrials.gov/ct2/show/NCT01371617?term=NCT01371617&rank=1

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.