Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin

Abstract

Phosphoinositide 3-kinase R (PI3KR) 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 PI3KR 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. KEYWORDS GSK2126458, phosphoinositide 3-kinase R, mammalian target of rapamycin, PI3K/AKT pathway

SWFB and GA Strategies for Variable Selection in QSAR Studies for the Validation of Thiazolidine- 2,4-Dione Derivatives as Promising Antitumor Candidates

“…[3][4] Recently, substituted-TZDs have been reported as PIM-2 enzyme inhibitors which have perspectives in the management of mutant cancer forms. 5 In various literature, 5-arylidene-thiazolidine-2,4-dione derivatives consisting of substituents at para or meta position of the benzylidene moiety have been identified to produce anticancer activity.…”

Overcoming resistance: Targeting the PI3K/mTOR pathway in endocrine refractory breast cancer

“…15,16 In the current issue of Cancer Biology & Therapy, 17 Leung and colleagues used cell models of AE resistance derived from the hormone-responsive breast cancer line, MCF-7 to explore the cellular effects of two dual PI3K/mTOR inhibitors-NVP-BEZ235 (BEZ235) 18 and GSK2126458 (GSK212). 19 The authors had previously developed cellular models of resistance to TAM and AIs by prolonged culturing of MCF-7 cells in increasing concentrations of TAM or in the absence of estrogen, respectively. 20 Interestingly, while the resultant sub-lines displayed some phenotypic heterogeneity, all were resistant to TAM irrespective of how they were derived, 20 suggesting that broad resistance to TAM and AIs may develop via the dysregulation of common, upstream signaling pathways.…”

“…20 Leung and colleagues extended this work in their more recent study to determine the effect of AE resistance on the cellular response to the PI3K/mTOR inhibitors, BEZ235 and GSK212. 17 Both of these compounds are highly specific and potent small molecule inhibitors with efficacy against both class I PI3K isoforms and mTOR kinase activity, 18,19 that are currently being evaluated in phase I/II clinical trials either in breast cancer patients with advanced disease (BEZ235), or solid tumors and lymphomas (GSK212). The MCF-7 cell line is an appropriate preclinical model to examine the efficacy of these agents as not only is it an established and well characterized model of ER-positive, luminal breast cancer, but it also harbors a mutation in the helical domain of PI3KCA, 21 which encodes the catalytic (p110a) subunit of P13K.…”

Synthesis of N-methylthieno [2, 3-d] Pyrimidin-4-amine Thienopyrimidine

“…At the same times, some literature have reported that the thienopyrimidine core can be used in preparing potent P2Y12 inhibitors [6]. For example, GDC-0941 and BKM 120 are a selective PI3K inhibitors which have been advanced into clinical evaluation [7][8][9][10]. At the same times, some literature point out 2-substituted thienopirimidin-4-one derivatives may serve as novel spasmolytic agents to treat disorders of smooth muscle function, and those compounds have a common features that are thieno [2,3-d] pyrimidin [11], the structure of thieno [2,3-d]pyrimidin and target compound was shown in Fig.…”