The pre-clinical absorption, distribution, metabolism and excretion properties of IPI-926, an orally bioavailable antagonist of the hedgehog signal transduction pathway

Smith, Sherri; Hoyt, Jennifer; Whitebread, Nigel; Manna, Joseph; Peluso, Marisa; Faia, Kerrie; Campbell, Veronica T.; Tremblay, Martin; Nair, Somarajan; Grogan, Michael J.; Castro, Alfredo; Campbell, Matthew; Ferguson, J; Arsenault, Brendan; Nevejans, Jylle; Carter, Bennett; Lee, John; Dunbar, Joi; McGovern, Karen; Read, Margaret; Adams, Julian; Constan, Alexander A.; Loewen, Gordon; Sydor, Jens; Palombella, Vito J.; Soglia, John R.

doi:10.3109/00498254.2013.780671

Cited by 4 publications

(3 citation statements)

References 29 publications

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“…Another derivative of cyclopamine is Saridegib (IPI-926), which has shown antitumor activity in models of medulloblastoma, ovarian cancer, chondrosarcoma, and osteosarcoma (138)(139)(140)(141)(142). There have been early stage clinical trials with Saridegib that have shown favorable pharmacodynamics and pharmacokinetics while having some antitumor activity toward solid tumors (143)(144)(145)(146). However, Saridegib was not recommended for further developing in patients with myelofibrosis or pancreatic cancer (145,147).…”

Section: Agents Targeting Smomentioning

confidence: 99%

Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer

Carpenter

Ray

2019

Drug Saf

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The hedgehog pathway, for which sonic hedgehog (Shh) is the most prominent ligand, is highly conserved and is tightly associated with embryonic development in a number of species. This pathway is also tightly associated with development of several types of cancer, including basal cell carcinoma and acute promyelocytic leukemia (APL) among many others. Inactivating mutations in Patched 1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types but most prominent in basal cell carcinoma. This has led to the development of several compounds targeting this pathway as a cancer therapeutic. These compounds target the inducers of this pathway in Smoothened (SMO) and the GLI transcription factors, although targeting SMO has had the most success. Despite the many attempts at targeting this pathway, there are only three FDA-approved drugs for cancers that affect the Shh pathway. Two of these compounds, vismodegib and sonidegib, target SMO to suppress signaling from either PTCH1 or SMO mutations that lead to upregulation of the pathway. The other approved compound is arsenic trioxide (ATO), which can suppress this pathway at the level of the GLI proteins, although current evidence suggests it also has other targets. This review focuses on the efficacy and safety of these clinically-approved drugs targeting the Shh pathway along with a discussion on other Shh pathway inhibitors being developed.

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Section: Agents Targeting Smomentioning

confidence: 99%

Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer

Carpenter

Ray

2019

Drug Saf

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“…56,57 The most promising targeted therapy, IPI-926, is a semisynthetic small-molecule inhibitor derivative of the alkaloid cyclopamine that inhibits the hedgehog pathway by binding to and inhibiting Smoothened and thus keeping Gli inactive. 58 Olive et al, 59 in an exciting preclinical study, showed IPI-926 enhanced perfusion of gemcitabine within the pancreatic tumor and improved survival. In this study, IPI-926 decreased collagen 1 in the stroma and proliferation of a-SMA stromal cells and transiently increased blood vessel density in the tumors using a KPC mouse model.…”

Section: Hedgehogmentioning

confidence: 99%

The Paradoxical Web of Pancreatic Cancer Tumor Microenvironment

Lafaro

Melstrom

2019

The American Journal of Pathology

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Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence and is projected to become the second leading cause of cancer death in the United States. Despite significant advances in understanding the disease, there has been minimal increase in PDAC patient survival. PDAC tumors are unique in the fact that there is significant desmoplasia. This generates a large stromal compartment composed of immune cells, inflammatory cells, growth factors, extracellular matrix, and fibroblasts, comprising the tumor microenvironment (TME), which may represent anywhere from 15% to 85% of the tumor. It has become evident that the TME, including both the stroma and extracellular component, plays an important role in tumor progression and chemoresistance of PDAC. This review will discuss the multiple components of the TME, their specific impact on tumorigenesis, and the multiple therapeutic targets.

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“…Interestingly, saridegib is active in cells with the D473H point mutation that renders them resistant to vismodegib [145]. Although saridegib showed desirable preclinical absorption, distribution, metabolism, and excretion properties [147], and a phase I study in adult patients with solid tumors demonstrated a good pharmacokinetic profile [148], it has been discontinued for lack of response [149,150].…”

Section: Smoothened Inhibitorsmentioning

confidence: 99%

Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors

Pietrobono¹,

Stecca²

2018

Cells

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Hedgehog-GLI (HH) signaling was originally identified as a critical morphogenetic pathway in embryonic development. Since its discovery, a multitude of studies have reported that HH signaling also plays key roles in a variety of cancer types and in maintaining tumor-initiating cells. Smoothened (SMO) is the main transducer of HH signaling, and in the last few years, it has emerged as a promising therapeutic target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been hampered by severe side effects, low selectivity against cancer stem cells, and the onset of mutation-driven drug resistance. Moreover, SMO antagonists are not effective in cancers where HH activation is due to mutations of pathway components downstream of SMO, or in the case of noncanonical, SMO-independent activation of the GLI transcription factors, the final mediators of HH signaling. Here, we review the current and rapidly expanding field of SMO small-molecule inhibitors in experimental and clinical settings, focusing on a class of acylguanidine derivatives. We also discuss various aspects of SMO, including mechanisms of resistance to SMO antagonists.

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The pre-clinical absorption, distribution, metabolism and excretion properties of IPI-926, an orally bioavailable antagonist of the hedgehog signal transduction pathway

Cited by 4 publications

References 29 publications

Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer

Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer

The Paradoxical Web of Pancreatic Cancer Tumor Microenvironment

Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors

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