Small‐Molecule Inhibitors of the Hedgehog Signaling Pathway as Cancer Therapeutics

Lee

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

et al. 2010

285

244

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.

Section: Discussionmentioning

confidence: 99%

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

Lee

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

et al. 2010

285

244

“…5 Both of these compounds inhibit the Hh pathway by directly binding Smoothened (SMO), a key regulator of pathway signaling and the most druggable target within the pathway. GDC-0449 recently received fast-track approval by the FDA for the treatment of metastatic BCC, representing the first Hh pathway inhibitor to receive FDA approval and validating the clinical relevance of targeting aberrant Hh signaling.…”

mentioning

confidence: 99%

Identification of Vitamin D3-Based Hedgehog Pathway Inhibitors That Incorporate an Aromatic A-Ring Isostere

DeBerardinis

Banerjee

Hadden

2013

ACS Med. Chem. Lett.

Previous structure−activity relationship studies for vitamin D3 (VD3) inhibition of Hedgehog (Hh) signaling directed the design, synthesis, and evaluation of a series of VD3-based analogues that contain an aromatic A-ring mimic. Characterization of these compounds in a series of cellular assays demonstrated their ability to potently and selectively downregulate Hh pathway signaling. The most active of these, 17, inhibited pathway signaling in Hh-dependent mouse fibroblasts (IC 50 = 0.74 ± 0.1 μM) and cultured cancer cells (IC 50 values 3.8 ± 0.1 to 5.2 ± 0.2 μM). In addition, 17 demonstrated reduced activation of the vitamin D receptor (VDR) compared to VD3 in these cellular models. These results suggest that VD3-based analogues with an aromatic A-ring are a valid scaffold for the development of more selective and potent Hh pathway inhibitors and identify 17 as an intriguing lead from this class of compounds for further development. In addition, our analysis of Hh pathway inhibitors in cancer cells suggests that the murine basal cell carcinoma cell line ASZ001 and the human medulloblastoma cell line DAOY are appropriate in vitro cancer models for early stage evaluation of pathway inhibition.

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

“…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).…”

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confidence: 99%

“…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). Smo agonists, including the small molecule Smoothened agonist (SAG), have been identified as well (18).…”

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confidence: 99%

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

Chen

Arkin

et al. 2012

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.