Discovery of 4-morpholino-pyrimidin-6-one and 4-morpholino-pyrimidin-2-one-containing Phosphoinositide 3-kinase (PI3K) p110β isoform inhibitors through structure-based fragment optimisation

Giordanetto, Fabrizio; Wållberg, Andreas; Cassel, Johan; Ghosal, Saswati; Kossenjans, Michael; Yuan, Zhong-Qing; Wang, Xiaoping; Liang, Lifeng

doi:10.1016/j.bmcl.2012.08.101

Cited by 20 publications

(13 citation statements)

References 33 publications

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“…From these structures, two regions lining the active site, an inducible hydrophobic “selectivity” pocket and an “affinity” pocket, were identified that are thought to contribute to the binding properties of a given ligand. It appears serendipity of target choice and the unique plasticity of the PIK3 active site rather than design have played the key roles in the development of selective PI3K competitive inhibitors as efforts to find further isoform-selective inhibitors using fragment-based screening methods have also produced compounds that target the active site (Giordanetto et al, 2011 , 2012 ; Hughes et al, 2011 ).…”

Section: Inhibitors Of Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

“…Selectivity has been a major stumbling block in drugging PI3K since a large number of sequence-conserved isoforms play distinct yet overlapping functions within the cell (Vanhaesebroeck et al, 2010 ). However, as with Ras, computational chemistry techniques and FBDD have helped develop some promising new avenues in selectively targeting various isoforms (Giordanetto et al, 2011 , 2012 ; Hughes et al, 2011 ), albeit through competitive inhibitors that bind the active site. Selective PI3K inhibition by allosteric means may soon emerge from recent reports that have begun to decipher the activation mechanism of these enzymes (Burke et al, 2012 ; Hon et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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Allosteric modulation of Ras and the PI3K/AKT/mTOR pathway: emerging therapeutic opportunities

2014

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GTPases and kinases are two predominant signaling modules that regulate cell fate. Dysregulation of Ras, a GTPase, and the three eponymous kinases that form key nodes of the associated phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K)/AKT/mTOR pathway have been implicated in many cancers, including pancreatic cancer, a disease noted for its current lack of effective therapeutics. The K-Ras isoform of Ras is mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC) and there is growing evidence linking aberrant PI3K/AKT/mTOR pathway activity to PDAC. Although these observations suggest that targeting one of these nodes might lead to more effective treatment options for patients with pancreatic and other cancers, the complex regulatory mechanisms and the number of sequence-conserved isoforms of these proteins have been viewed as significant barriers in drug development. Emerging insights into the allosteric regulatory mechanisms of these proteins suggest novel opportunities for development of selective allosteric inhibitors with fragment-based drug discovery (FBDD) helping make significant inroads. The fact that allosteric inhibitors of Ras and AKT are currently in pre-clinical development lends support to this approach. In this article, we will focus on the recent advances and merits of developing allosteric drugs targeting these two inter-related signaling pathways.

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Section: Inhibitors Of Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Allosteric modulation of Ras and the PI3K/AKT/mTOR pathway: emerging therapeutic opportunities

2014

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“…In the following study, authors aimed to improve the affinity of the compound (1) by substituting the dimethylamino group with a more voluminous 2-(benzylamino) moiety (Giordanetto et al, 2012). The novel compound (2) showed improved potency (IC 50 = 1.9 µM) and efficiency (LE = 0.37 and LLE = 4.52) toward p110β.…”

Section: Case Studies Identification Of Pi3k P110β Selective Fragmentmentioning

confidence: 99%

In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs

et al. 2020

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Rational drug design implies usage of molecular modeling techniques such as pharmacophore modeling, molecular dynamics, virtual screening, and molecular docking to explain the activity of biomolecules, define molecular determinants for interaction with the drug target, and design more efficient drug candidates. Kinases play an essential role in cell function and therefore are extensively studied targets in drug design and discovery. Kinase inhibitors are clinically very important and widely used antineoplastic drugs. In this review, computational methods used in rational drug design of kinase inhibitors are discussed and compared, considering some representative case studies.

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“…The β/δ selectivity of these series is diminished compared with the original PI3Kβ selective inhibitor TGX-221, suggesting smaller substituents are favored by PI3Kβ [15]. However, in a study focusing on PI3Kβ/α selectivity, bulkier substituents were found to increase the selectivity over PI3Kα [126].…”

Section: Structural Determinants Of Isoform Selectivitymentioning

confidence: 99%

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Miller

Thompson²,

Gabelli

2019

Biomolecules

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Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3K, PI3K, PI3K and PI3K have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.

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Discovery of 4-morpholino-pyrimidin-6-one and 4-morpholino-pyrimidin-2-one-containing Phosphoinositide 3-kinase (PI3K) p110β isoform inhibitors through structure-based fragment optimisation

Cited by 20 publications

References 33 publications

Allosteric modulation of Ras and the PI3K/AKT/mTOR pathway: emerging therapeutic opportunities

Allosteric modulation of Ras and the PI3K/AKT/mTOR pathway: emerging therapeutic opportunities

In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

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