Synthesis and biological evaluation of SANT-2 and analogues as inhibitors of the hedgehog signaling pathway

Büttner, Anita; Seifert, Katrin; Cottin, Thomas; Sarli, Vasiliki; Tzagkaroulaki, Lito; Scholz, Stefan; Giannis, Athanassios

doi:10.1016/j.bmc.2009.06.008

Cited by 42 publications

(30 citation statements)

References 24 publications

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“…These chemical compounds include the natural plant-derived steroidal alkaloid cyclopamine and its derivatives, such as 3-keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl) cyclopamine (KAAD-cyclopamine), and semisynthetic D-homo-ring analogs IPI-269609 (Feldmann et al, 2008) and IPI-926 (Olive et al, 2009) as well as small synthetic molecules such as 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide (GDC-0049; HhAntag691), a proline derivative Cur61414 (Rubin and de Sauvage, 2006), and N-(6-((2S,6R) (Table 1) (Williams et al, 2003;Romer et al, 2004;Mimeault et al, 2006;Riobo et al, 2006a;Rubin and de Sauvage, 2006;Bar et al, 2007;Chen et al, 2007b;Clement et al, 2007;Lauth et al, 2007;Peacock et al, 2007;Stecca et al, 2007;Feldmann et al, 2008;Bü ttner et al, 2009;Eichenmü ller et al, 2009;Jimeno et al, 2009;Olive et al, 2009;Robarge et al, 2009;Tremblay et al, 2009;Mimeault and Batra, 2010b;Pan et al, 2010;Stanton and Peng, 2010;Yang et al, 2010). Moreover, small synthetic structural analogs of the second and third intracellular loops of the SMO proteins, such as small palmitoylated peptides as short as 10 residues, have also been designed (Remsberg et al, 2007).…”

Section: A Targeting Of the Canonical Hedgehog Tumorigenic Signalingmentioning

confidence: 99%

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

2010

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Section: A Targeting Of the Canonical Hedgehog Tumorigenic Signalingmentioning

confidence: 99%

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

2010

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“…Robotnikinin is an inhibitor of Sonic hedgehog (Shh) activity, and GANT61, JK184 and HPI4 inhibit Gli transcription factors (18)(19)(20)(21), but the majority of identified Hh pathway antagonists inhibit Smo. These include cyclopamine (a natural steroidal alkaloid), Cur61414, Vismodegib/ GDC-0449, and LDE225 (22)(23)(24)(25). Vismodegib is approved for the treatment of BCC (24).…”

mentioning

confidence: 99%

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

Chen

Arkin

et al. 2012

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

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Vertebrate Hedgehog (Hh) signals involved in development and some forms of cancer, such as basal cell carcinoma, are transduced by the primary cilium, a microtubular projection found on many cells. A critical step in vertebrate Hh signal transduction is the regulated movement of Smoothened (Smo), a seven-transmembrane protein, to the primary cilium. To identify small molecules that interfere with either the ciliary localization of Smo or ciliogenesis, we undertook a high-throughput, microscopy-based screen for compounds that alter the ciliary localization of YFP-tagged Smo. This screen identified 10 compounds that inhibit Hh pathway activity. Nine of these Smo antagonists (SA1–9) bind Smo, and one (SA10) does not. We also identified two compounds that inhibit ciliary biogenesis, which block microtubule polymerization or alter centrosome composition. Differential labeling of cell surface and intracellular Smo pools indicates that SA1–7 and 10 specifically inhibit trafficking of intracellular Smo to cilia. In contrast, SA8 and 9 recruit endogenous Smo to the cilium in some cell types. Despite these different mechanisms of action, all of the SAs inhibit activation of the Hh pathway by an oncogenic form of Smo, and abrogate the proliferation of basal cell carcinoma-like cancer cells. The SA compounds may provide alternative means of inhibiting pathogenic Hh signaling, and our study reveals that different pools of Smo move into cilia through distinct mechanisms.

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“…Other novel Smo inhibitors that are undergoing preclinical testing include SANT1-4 [95,96], Hh Antag [97,98]; and IPI-269609 [99,100]. In addition, naturally occurring molecules such as vitamin D 3 [101,102] (see below) and drugs currently used to treat other diseases – such as itraconazole, a commonly used antifungal drug [103] (see below) – have been suggested to be Smo antagonists.…”

Section: Mechanism-based Therapy: Hedgehog Pathway Inhibitorsmentioning

confidence: 99%

Novel investigational drugs for basal cell carcinoma

So¹,

Tang

Epstein³

2010

Expert Opinion on Investigational Drugs

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Importance of the field In the United States, the annual incidence of basal cell carcinoma (BCC) is close to 1 million. Ultraviolet radiation exposure is the main risk factor; however, the availability of ever more potent sunscreens and education have not prevented the rise in BCC incidence. Therefore, concerted effects to identify novel preventive and therapeutic strategies are necessary. Areas covered in this review This article summarizes our current understanding of the etiology and molecular mechanisms of BCC tumorigenesis and discusses the preclinical and clinical studies to identify agents with anti-BCC efficacy. What the reader will gain The discovery that hyperactive Hh pathway signaling causes several cancers, including BCC, has spawned the development of many pharmacologic inhibitors of Hh signaling. Early clinical testing of the most advanced, GDC-0449, demonstrated impressive efficacy in patients with advanced BCC. Other promising anti-BCC chemopreventive strategies include drugs that are already FDA-approved for treating other diseases. Take home message Preclinical and clinical trials with pre-existing FDA-approved drugs suggest novel uses for BCC chemoprevention and treatment. Also, new chemical entities that inhibit the Hh pathway show promise, and in combination with other drugs may provide a nonsurgical cure for this most common cancer.

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Synthesis and biological evaluation of SANT-2 and analogues as inhibitors of the hedgehog signaling pathway

Cited by 42 publications

References 24 publications

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

Novel investigational drugs for basal cell carcinoma

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