GDC-0449—A potent inhibitor of the hedgehog pathway

Robarge, Kirk; Brunton, Shirley A.; Castanedo, Georgette; Cui, Yong; Dina, Michael S.; Goldsmith, Richard; Gould, Stephen E.; Guichert, Oivin; Gunzner, Janet L.; Halladay, Jason; Jia, Wei; Khojasteh, Cyrus; Koehler, Michael F. T.; Kotkow, Karen; La, Hank; LaLonde, Rebecca Lyn; Lau, Kevin; Lee, Leslie; Marshall, Derek; Marsters, James C.; Murray, Lesley J.; Qian, Changgeng; Rubin, Lee L.; Salphati, Laurent; Stanley, Mark; Stibbard, John H. A.; Sutherlin, Daniel P.; Ubhayaker, Savita; Wang, Shumei; Wong, Susan; Xie, Minli

doi:10.1016/j.bmcl.2009.08.049

Cited by 354 publications

(242 citation statements)

References 20 publications

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“…Cyclopamine mimics are currently in wide development in the pharmaceutical industry (36,37,63,64) but are not expected to be effective in diseases in which pathway activation involves mutations in components downstream of Smo (13)(14)(15)41) or in which pathway activity results from increased expression or activity of the Gli1 proteins (16)(17)(18)(19)25). In addition, mutations that cause constitutive Smo activity can render Smo resistant to the action of cyclopamine mimics (11,30), or resistance can arise in the setting of treatment with a cyclopamine mimic, as has been documented for a human medulloblastoma patient (38,40).…”

Section: Discussionmentioning

confidence: 99%

“…A number of additional Hh antagonists subsequently identified in vitro in signaling assays by screening of chemical libraries appear to mimic cyclopamine in binding to Smo (32,33), and most compete with a fluorescent derivative of cyclopamine for binding to Smo. Smo thus appears to represent the major target in screens for Hh pathway antagonists, and cyclopamine mimics or cyclopamine derivatives have been the major focus of efforts to develop drugs that target the Hh signaling pathway (34)(35)(36)(37); one of these candidates, GDC-0449, appears to be remarkably effective in recent clinical trials (38,39).…”

mentioning

confidence: 99%

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Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector

Kim

Lee

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

287

244

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Aberrant Hedgehog (Hh) pathway activation has been implicated in cancers of diverse tissues and organs, and the tumor growth-inhibiting effects of pathway antagonists in animal models have stimulated efforts to develop pathway antagonists for human therapeutic purposes. These efforts have focused largely on cyclopamine derivatives or other compounds that mimic cyclopamine action in binding to and antagonizing Smoothened, a membrane transductory component. We report here that arsenicals, in contrast, antagonize the Hh pathway by targeting Gli transcriptional effectors; in the short term, arsenic blocks Hh-induced ciliary accumulation of Gli2, the primary activator of Hh-dependent transcription, and with prolonged incubation arsenic reduces steady-state levels of Gli2. Arsenicals active in Hh pathway antagonism include arsenic trioxide (ATO), a curative agent in clinical use for acute promyelocytic leukemia (APL); in our studies, ATO inhibited growth of Hh pathway-driven medulloblastoma allografts derived from Ptch +/− p53 −/− mice within a range of serum levels comparable to those achieved in treatment of human APL. Arsenic thus could be tested rapidly as a therapeutic agent in malignant diseases associated with Hh pathway activation and could be particularly useful in such diseases that are inherently resistant or have acquired resistance to cyclopamine mimics.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector

Kim

Lee

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

287

244

View full text Add to dashboard Cite

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“…A major breakthrough is the recent approval of a novel Smo antagonist Erivedge/Vismodegib (GDC-0449) in the Shh field by the FDA for treating metastatic BCC and locally advanced BCC deemed untreatable by surgery or radiation (Robarge et al, 2009). However, its effects in kidney diseases remain to be investigated and validated in the preclinical setting before considering any clinic trials.…”

Section: Strategies To Target Shh Signaling In Kidney Fibrosismentioning

confidence: 99%

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Zhou

Tan

Liu

2016

Sci. China Life Sci.

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The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog (Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease (CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelial-mesenchymal communication (EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.

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“…This finding provides an opportunity for specifically targeting CSCs which are responsible for tumor initiation, progression, recurrence and metastasis (Curtin and Lorenzi, 2010). Significant progress has been made in developing therapeutics targeting Notch and Hh (Luistro et al, 2009;Robarge et al, 2009), whereas the Wnt pathway has been more challenging for targeted therapy (Curtin and Lorenzi, 2010).…”

Section: 2789 Application Of Stem Cells In Targeted Therapy Of Breasmentioning

confidence: 99%

Application of Stem Cells in Targeted Therapy of Breast Cancer: A Systematic Review

Madjd

Gheytanchi²,

Erfani³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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GDC-0449—A potent inhibitor of the hedgehog pathway

Cited by 354 publications

References 20 publications

Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector

Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Application of Stem Cells in Targeted Therapy of Breast Cancer: A Systematic Review

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