ipi-926 and cyclopamine

The Hedgehog signalling pathway plays a critical role in controlling growth, especially during development, but is often over-activated in tumourigenesis. It has recently emerged as an important target for anticancer drugs, with several compounds in clinical trials. This review initially describes the Hedgehog pathway, focussing on the Patched receptor, and the Smoothened GPCR-like protein, as well as discussing the role of Cancer Stem Cells. It subsequently presents the discovery and development of drugs targeting this pathway. The initial focus is on cyclopamine - the first compound discovered that could inhibit the Hedgehog pathway - and selected cyclopamine analogues, including a review of the development of IPI-926. In addition, a number of other compounds are briefly discussed, to give an overview of current therapies in clinical development, and to indicate the possibilities for targeting different parts of the Hedgehog pathway in future. Finally, combination chemotherapy - incorporating a Hedgehog pathway inhibitor as well as another drug - is discussed from the perspective of drug resistance and effects on cancer stem cells.

Topics: Antineoplastic Agents; Hedgehog Proteins; Humans; Neoplasms; Neoplastic Stem Cells; Signal Transduction; Veratrum Alkaloids

Sonic hedgehog (Shh) is the most widely characterized of the three vertebrate Hedgehog homologs, and is essential for proper embryonic development. Shh binds to its receptor, Patched (Ptch1), resulting in the de-repression of Smoothened (Smo). This leads to the activation of Gli2, which regulates the transcription of target genes that include Gli1 and Ptch1. Several synthetic and naturally occurring small-molecule modulators of Smo have been discovered. Shh-signaling antagonists that bind to Smo include cyclopamine, SANT1, and Cur-61414. Shh signaling agonists that bind to Smo include the synthetic small molecules purmorphamine and SAG. Small molecules that inhibit Shh signaling downstream of Smo, GANT58 and GANT61 have also been reported. Robotnikinin inhibits the Shh pathway by directly targeting Shh. Although progress has been made in understanding and modulating Shh signaling, fundamental aspects of Shh signal transduction remain obscure, including the mechanism(s) whereby Ptch1 regulates Smo activity. Small-molecule modulators of Shh signaling provide a means to regulate the activity of a pathway implicated in medulloblastoma, basal cell carcinoma (BCC), pancreatic cancer, prostate cancer and developmental disorders. Several Shh inhibitors have not succeeded in the clinic for unknown reasons, but clinical trials in BCC and pancreatic cancer with the promising Smo antagonists GDC-0449 and IPI-926 are currently underway.

Topics: Anilides; Animals; Dioxoles; Hedgehog Proteins; Humans; Models, Biological; Molecular Structure; Piperazines; Pyrazoles; Pyridines; Receptors, G-Protein-Coupled; Signal Transduction; Smoothened Receptor; Thiophenes; Veratrum Alkaloids

Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.. We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.. Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C), no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.. IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.

Topics: Animals; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Maintenance Chemotherapy; Mice; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; RNA, Messenger; Signal Transduction; Stromal Cells; Survival Analysis; Transcription Factors; Veratrum Alkaloids; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1

Conserved embryonic signaling pathways such as Hedgehog (Hh), Wingless and Notch have been implicated in the pathogenesis of several malignancies. Recent data suggests that Hh signaling plays a role in normal B-cell development, and we hypothesized that Hh signaling may be important in precursor B-cell acute lymphocytic leukemia (B-ALL). We found that the expression of Hh pathway components was common in human B-ALL cell lines and clinical samples. Moreover, pathway activity could be modulated by Hh ligand or several pathway inhibitors including cyclopamine and the novel SMOOTHENED (SMO) inhibitor IPI-926. The inhibition of pathway activity primarily impacted highly clonogenic B-ALL cells expressing aldehyde dehydrogenase (ALDH) by limiting their self-renewal potential both in vitro and in vivo. These data demonstrate that Hh pathway activation is common in B-ALL and represents a novel therapeutic target regulating self-renewal and persistence of the malignant clone.

Topics: Aldehyde Dehydrogenase; Animals; Antigens, CD19; Antigens, CD34; Antineoplastic Agents; Cell Line, Tumor; Hedgehog Proteins; Humans; Mice; Mice, SCID; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, G-Protein-Coupled; Signal Transduction; Smoothened Receptor; Veratrum Alkaloids

Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Cell Line; Drug Discovery; Hedgehog Proteins; Humans; Liver; Medulloblastoma; Microsomes; Signal Transduction; Stereoisomerism; Veratrum Alkaloids