Structure-based optimization of pyrazolo-pyrimidine and -pyridine inhibitors of PI3-kinase

Staben, Steven T.; Heffron, Timothy P.; Sutherlin, Daniel P.; Bhat, Seema R.; Castanedo, Georgette; Chuckowree, Irina; Dotson, Jenna; Folkes, Adrian; Friedman, Lori S.; Lee, Leslie; Lesnick, John; Lewis, Cristina; Murray, J.M.; Nonomiya, Jim; Olivero, Alan G.; Plise, Emile G.; Pang, Jodie; Prior, Wei Wei; Salphati, Laurent; Rougé, Lionel; Sampath, Deepak; Tsui, Vickie; Wan, Nan Chi; Wang, Shumei; Weismann, Christian; Wu, Ping; Zhu, Bing‐Yan

doi:10.1016/j.bmcl.2010.08.067

Cited by 26 publications

(9 citation statements)

References 24 publications

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“…Staben et al have reported on the characterization of the p110α inhibitors 73 and 74 , which have respective IC 50 s of 162nM and 6.8nM, and which display potent pharmacodynamic biomarker modulatory activity in vitro, notablyeffect s onphosphorylation of AKT, PRAS40 and RPS6, in PC3 prostate cancer cells [92]. …”

Section: Isoform-selective Pi3k Inhibitors: Historical Landscape and mentioning

confidence: 99%

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

Shuttleworth

Silva²,

Cecil³

et al. 2011

CMC

100

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The phosphoinositide 3-kinases (PI3Ks) constitute an important family of lipid kinase enzymes that control a range of cellular processes through their regulation of a network of signal transduction pathways, and have emerged as important therapeutic targets in the context of cancer, inflammation and cardiovascular diseases. Since the mid-late 1990s, considerable progress has been made in the discovery and development of small molecule ATP-competitive PI3K inhibitors, a number of which have entered early phase human trials over recent years from which key clinical results are now being disclosed. This review summarizes progress made to date, primarily on the discovery and characterization of class I and dual class I/IV subtype inhibitors, together with advances that have been made in translational and clinical research, notably in cancer.

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Section: Isoform-selective Pi3k Inhibitors: Historical Landscape and mentioning

confidence: 99%

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

Shuttleworth

Silva²,

Cecil³

et al. 2011

CMC

100

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“…Considering these two factors, it is not surprising that binding data related to congeneric series (as discussed for several examples below) suggest congeners to be relatively susceptible to substitutions in the region exposed to solvent. Optimization of potency through the solvent exposed parts of small molecules has become an interesting challenge in the discovery of active compounds. − …”

Section: Resultsmentioning

confidence: 99%

Structural Isosteres of Phosphate Groups in the Protein Data Bank

Zhang¹,

Borrel

Ghemtio³

et al. 2017

J. Chem. Inf. Model.

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We developed a computational workflow to mine the Protein Data Bank for isosteric replacements that exist in different binding site environments but have not necessarily been identified and exploited in compound design. Taking phosphate groups as examples, the workflow was used to construct 157 data sets, each composed of a reference protein complexed with AMP, ADP, ATP, or pyrophosphate as well other ligands. Phosphate binding sites appear to have a high hydration content and large size, resulting in U-shaped bioactive conformations recurrently found across unrelated protein families. A total of 16 413 replacements were extracted, filtered for a significant structural overlap on phosphate groups, and sorted according to their SMILES codes. In addition to the classical isosteres of phosphate, such as carboxylate, sulfone, or sulfonamide, unexpected replacements that do not conserve charge or polarity, such as aryl, aliphatic, or positively charged groups, were found.

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“…At the onset of this program, we had ready access to many potent PI3K and PI3K/mTOR inhibitors (Folkes et al, 2008;Heffron et al, 2011;Ndubaku et al, 2013;Staben et al, 2010Staben et al, , 2011Staben et al, , 2013aSutherlin et al, 2010Sutherlin et al, , 2011. Unique to this program for the treatment of retinal diseases, we wanted to ensure that the solubility was high enough to ensure the ability to sustain concentrations in the vitreous humor (to allow access to retina) 10-fold over the cellular EC 50 .…”

Section: Discussionmentioning

confidence: 99%

Characterization of Antineovascularization Activity and Ocular Pharmacokinetics of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GNE-947

et al. 2020

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The objectives of the present study were to characterize GNE-947 for its phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitory activities, in vitro anti-cell migration activity in human umbilical vein endothelial cells (HUVECs), in vivo antineovascularization activity in laser-induced rat choroidal neovascular (CNV) eyes, pharmacokinetics in rabbit plasma and eyes, and ocular distribution using matrix-assisted laser desorption/ ionization imaging mass spectrometry (MALDI-IMS) and autoradioluminography. Its PI3K and mTOR K i were 0.0005 and 0.045 mM, respectively, and its HUVEC IC 50 was 0.093 mM. GNE-947 prevented neovascularization in the rat CNV model at 50 or 100 mg per eye with repeat dosing. After a single intravenous injection at 2.5 and 500 mg/kg in rabbits, its plasma terminal half-lives (t 1/2 ) were 9.11 and 9.59 hours, respectively. After a single intravitreal injection of a solution at 2.5 mg per eye in rabbits, its apparent t 1/2 values were 14.4, 16.3, and 23.2 hours in the plasma, vitreous humor, and aqueous humor, respectively. After a single intravitreal injection of a suspension at 33.5, 100, 200 mg per eye in rabbits, the t 1/2 were 29, 74, and 219 days in the plasma and 46, 143, and 191 days in the eyes, respectively. MALDI-IMS and autoradioluminography images show that GNE-947 did not homogenously distribute in the vitreous humor and aggregated at the injection sites after injection of the suspension, which was responsible for the long t 1/2 of the suspension because of the slow dissolution process. This hypothesis was supported by pharmacokinetic modeling analyses. In conclusion, the PI3K/mTOR inhibitor GNE-947 prevented neovascularization in a rat CNV model, with t 1/2 up to approximately 6 months after a single intravitreal injection of the suspension in rabbit eyes. SIGNIFICANCE STATEMENTGNE-947 is a potent phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor and exhibits anti-choroidal neovascular activity in rat eyes. The duration of GNE-947 in the rabbit eyes after intravitreal injection in a solution is short, with a half-life (t 1/2 ) of less than a day. However, the duration after intravitreal dose of a suspension is long, with t 1/2 up to 6 months due to low solubility and slow dissolution. These results indicate that intravitreal injection of a suspension for low-solubility drugs can be used to achieve long-term drug exposure.

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Structure-based optimization of pyrazolo-pyrimidine and -pyridine inhibitors of PI3-kinase

Cited by 26 publications

References 24 publications

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

Structural Isosteres of Phosphate Groups in the Protein Data Bank

Characterization of Antineovascularization Activity and Ocular Pharmacokinetics of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GNE-947

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