Inhibitors of phosphoinositide-3-kinase: a structure-based approach to understanding potency and selectivity

Sundstrom, Teather J.; Anderson, Amy C.; Wright, Dennis L.

doi:10.1039/b819067b

Cited by 43 publications

(33 citation statements)

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“…Together with the serine/threonine protein kinase B (PKB), PI3Ks constitute a central signalling hub that mediates many diverse and crucial cell functions like cell growth, proliferation, metabolism and survival1,3. The observation that PI3Ks acting downstream of receptor tyrosine kinases (RTKs) are the most commonly mutated kinases in human cancers has spurred an immense interest in understanding the structural mechanisms how these mutations upregulate PI3K activity and in developing selective and drug-like PI3K inhibitors4,5.…”

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confidence: 99%

The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

et al. 2010

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Deregulation of the phosphoinositide 3-kinase (PI3K) pathway has been implicated in numerous pathologies like cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small molecule and ATP-competitive PI3K inhibitors with a wide range of selectivities have entered clinical development. In order to understand mechanisms underlying isoform selectivity of these inhibitors, we developed a novel expression strategy that enabled us to determine the first crystal structure of the catalytic subunit of the class IA PI3K p110δ. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI3K inhibitors reveal that selectivity towards p110δ can be achieved by exploiting its conformational flexibility and the sequence diversity of active-site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110δ with greatly improved potencies.

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confidence: 99%

The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

et al. 2010

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“…Liphagal 180 isolated from the methanol extract of the sponge Aka coralliphaga , collected from reefs in Prince Rupert Bay, Portsmouth, Dominica [264] exhibited impressive biological activity including inhibitory activity against PI3K a (phosphoinositide-3-kinase α) and cytotoxic to LoVo and CaCo human colon, and MDA-468 human breast tumor cell lines [264,265,266]. …”

Section: Furan Polyene Cationic Cyclizationmentioning

confidence: 99%

Synthetic Strategies to Terpene Quinones/Hydroquinones

Gordaliza

2012

Marine Drugs

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The cytotoxic and antiproliferative properties of many natural sesquiterpene-quinones and -hydroquinones from sponges offer promising opportunities for the development of new drugs. A review dealing with different strategies for obtaining bioactive terpenyl quinones/hydroquinones is presented. The different synthetic approches for the preparation of the most relevant quinones/hydroquinones are described.

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“…The binding mode observed crystallography was quite similar to the well established mode exploited by ATP-competitive inhibitors that target protein kinases (Figure 2). The binding pocket can be roughly divided into three zones: a central part normally occupied by the adenine-ring of ATP with two potential hydrogen bonds to the kinase ‘hinge’ region (Val882 N-H and Glu880 C=O) [30], a hydrophobic back-pocket that is typically exploited to obtain potency and selectivity, and a forward pocket that exits to solvent. The crystal structure of the morpholine-chromenone class of structures as exemplified by LY294002 demonstrates that the morpholine oxygen forms a hydrogen bond with the Val882 N-H, while the chromenone scaffold occupies the adenine binding site and the phenyl ring is directed out towards solvent.…”

Section: Atp-competitive Inhibitorsmentioning

confidence: 99%

mTOR mediated anti-cancer drug discovery

Liu

Thoreen

Wang

et al. 2009

Drug Discovery Today: Therapeutic Strategies

159

113

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Summary The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase and the founding member of a signaling pathway that regulates many fundamental features of cell growth and division. In cells, mTOR acts as the catalytic subunit of two functionally distinct complexes, called mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). Together, these complexes coordinate a variety of processes that include protein translation, autophagy, proliferation, survival and metabolism in response to nutrient, energy and growth factor signals. Consistent with its role as a growth-promoting pathway, numerous studies have found that Mtor signaling is hyper-activated in a broad spectrum of human cancers. In particular, mTORC2 is considered a primary effector of the phosphatidylinositol-3-kinase (PI3K) signaling pathway, which is mutated in a majority of human cancers, in part through its ability to phosphorylate and regulate the proto-oncogene Akt/PKB. Many biological functions of mTOR have been pharmacologically explored using the natural product rapamycin, an allosteric inhibitor that has been reviewed extensively elsewhere. This review will focus specifically on the development of small molecule ATP-competitive inhibitors of mTOR and their prospects as a targeted therapy.

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Inhibitors of phosphoinositide-3-kinase: a structure-based approach to understanding potency and selectivity

Cited by 43 publications

References 50 publications

The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

Synthetic Strategies to Terpene Quinones/Hydroquinones

mTOR mediated anti-cancer drug discovery

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