Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin
Steven D. Knight,Nicholas D. Adams,Joelle Lorraine Burgess,Amita M. Chaudhari,Michael G. Darcy,Carla A. Donatelli,Juan I. Luengo,Ken A. Newlander,Cynthia A. Parrish,Lance Ridgers,Martha A. Sarpong,Schmidt Stanley J,Glenn S. Van Aller,Jeffrey D. Carson,Melody Diamond,Patricia A. Elkins,Christine M. Gardiner,Eric Garver,Seth A. Gilbert,Richard R. Gontarek,Jeffrey R. Jackson,Kevin L. Kershner,Lusong Luo,Kaushik Raha,Christian S. Sherk,Chiu-Mei Sung,David Sutton,Peter J. Tummino,Ronald Wegrzyn,Kurt R. Auger,Dashyant Dhanak +30 more
TLDR
2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3- pyridinyl}benzenesulfonamide (GSK2126458, 1) has been identified as a highly potent, orally bioavailable inhibitor of PI3Kα and mTOR with in vivo activity in both pharmacodynamic and tumor growth efficacy models.Abstract:
Phosphoinositide 3-kinase α (PI3Kα) is a critical regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers. The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative efficacy of PI3K/AKT pathway inhibition. 2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458, 1) has been identified as a highly potent, orally bioavailable inhibitor of PI3Kα and mTOR with in vivo activity in both pharmacodynamic and tumor growth efficacy models. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer.read more
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Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K
Jessie Villanueva,Adina Vultur,John T. Lee,Rajasekharan Somasundaram,Mizuho Fukunaga-Kalabis,Angela K. Cipolla,Bradley Wubbenhorst,Xiaowei Xu,Phyllis A. Gimotty,Damien Kee,Ademi Santiago-Walker,Richard Letrero,Kurt D'Andrea,Anitha Pushparajan,James Hayden,Kimberly Dahlman Brown,Sylvie Laquerre,Grant A. McArthur,Jeffrey A. Sosman,Katherine L. Nathanson,Meenhard Herlyn +20 more
TL;DR: Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF- 1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors.
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Quinoline as a Privileged Scaffold in Cancer Drug Discovery
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TL;DR: In vitro and in vivo anticancer activities of quinoline and its analogs are focused on in the context of cancer drug development and refinement, and selective and specific activity against various cancer drug targets are reviewed.
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Targeting mTOR for cancer therapy
TL;DR: Recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy are updated and the mechanisms underlying the resistance to mTOR inhibitor in cancer cells are discussed.
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Autophagy: The spotlight for cellular stress responses.
TL;DR: The machinery of Autophagy, the molecular web that connects autophagy to various stress responses like inflammation, hypoxia, ER stress, and various other pathologic conditions is discussed.
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mTOR signaling in disease
Eva Dazert,Michael N. Hall +1 more
TL;DR: The target of rapamycin (TOR) is a highly conserved serine/threonine kinase and a central controller of cell growth, metabolism and aging
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Journal ArticleDOI
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