3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma

Xu, Rui; Wang, Keshi; Rizzi, James P.; Huang, Heli; Grina, Jonas; Schlachter, Stephen T.; Wang, Bin; Wehn, Paul M.; Yang, Hanbiao; Dixon, Darryl D.; Czerwiński, Robert; Du, Xiaoqiang; Ged, Emily L.; Han, Guangzhou; Tan, Huiling; Wong, Tai W.; Xie, Shanhai; Josey, John A.; Wallace, Eli M.

doi:10.1021/acs.jmedchem.9b00719

Cited by 152 publications

(109 citation statements)

References 51 publications

(87 reference statements)

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“…Recently, secondgeneration allosteric inhibitor of HIF-2a PT2977 (MK-6482) was identified. Compared to PT2385, PT2977 have increased potency and improved pharmacokinetic profile (157). The result of phase I/II trial of PT2977 in 55 patients with advanced RCCs revealed that 24% patients experienced a confirmed PR and 54% had SD, with a clinical benefit rate of 78%.…”

Section: Hifs Inhibitorsmentioning

confidence: 99%

The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma

et al. 2020

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Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including PHD, VHL, HIF-2A (EPAS1), and SDHx are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.

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Section: Hifs Inhibitorsmentioning

confidence: 99%

The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma

et al. 2020

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“…These small molecules allosterically block the binding of HIF2α to ARNT/HIFβ, thereby inhibiting their transcriptional activity (Scheuermann et al 2015). Recent reports have shown very promising results of these two molecules in ccRCC, with a clear decrease in tumor growth in vitro and in vivo and a reduction in the expression of HIF2α target genes (Chen et al 2016, Cho et al 2016, Xu et al 2019. ccRCC is another example where tumorigenesis is mediated via a process of 'pseudohypoxia' through VHL mutations (Nickerson et al 2008).…”

Section: Targeting Pseudohypoxiamentioning

confidence: 99%

Epigenetic and metabolic reprogramming of SDH-deficient paragangliomas

Moog

Lussey-Lepoutre

Favier

2020

Endocrine-Related Cancer

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Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors arising from the adrenal medulla or extra-adrenal paraganglia. Around 40% of all cases are caused by a germline mutation in a susceptibility gene, half of which being found in an SDHx gene (SDHA, SDHB, SDHC, SDHD or SDHAF2). They encode the four subunits and assembly factor of succinate dehydrogenase (SDH), a mitochondrial enzyme involved both in the tricarboxylic acid cycle and in the electron transport chain. SDHx mutations lead to the accumulation of succinate, which acts as an oncometabolite by inhibiting iron(II) and alpha-ketoglutarate dependent dioxygenases thereby regulating the cell's hypoxic response and epigenetic processes. Moreover, SDHx mutations induce cell metabolic reprogramming and redox imbalance. Major discoveries in PPGL pathophysiology have been made since the initial discovery of SDHD gene mutations in 2000, improving the understanding of their biology, and patient management. It indeed provides new opportunities for diagnostic tools and innovative therapeutic targets in order to improve the prognosis of patients affected by these rare tumors, in particular in the context of metastatic diseases associated with SDHB mutations. This review first describes an overview of the pathophysiology and then focuses on clinical implications of the epigenetic and metabolic reprogramming of SDH-deficient PPGL.

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“…The HIF-1α inhibitor digoxin, which exerts anti-cancer effects by reducing the protein levels of HIF-1α and its target genes (GLUT1, HK, and VEGF [66]) is currently in phase II clinical trials to treat several cancers, including head and neck cancer, Kaposi's sarcoma, and breast cancer [67]. The first-in-class HIF-2α inhibitors PT2385 and PT2977 reduce the hypoxia-induced expression of VEGF and other hypoxia-responsible genes by blocking HIF-2α dimerization and DNA binding [68,69]. These inhibitors are currently under evaluation in a phase I/II clinical trial for treating VHL-associated renal carcinoma (RCC) and advanced clear cell RCC [70,71].…”

Section: Prospective Therapeutic Applications Of Ncrnas As Hif Regulamentioning

confidence: 99%

The Roles of Hypoxia-Inducible Factors and Non-Coding RNAs in Gastrointestinal Cancer

Cho

Han

Hur

et al. 2019

Genes

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Hypoxia-inducible factors (HIFs) are transcription factors that play central roles in cellular responses against hypoxia. In most cancers, HIFs are closely associated with tumorigenesis by regulating cell survival, angiogenesis, metastasis, and adaptation to the hypoxic tumor microenvironment. Recently, non-coding RNAs (ncRNAs) have been reported to play critical roles in the hypoxic response in various cancers. Here, we review the roles of hypoxia-response ncRNAs in gastrointestinal cancer, with a particular focus on microRNAs and long ncRNAs, and discuss the functional relationships and regulatory mechanisms between HIFs and ncRNAs.

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3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma

Cited by 152 publications

References 51 publications

The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma

The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma

Epigenetic and metabolic reprogramming of SDH-deficient paragangliomas

The Roles of Hypoxia-Inducible Factors and Non-Coding RNAs in Gastrointestinal Cancer

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