Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties

Hoegenauer, Klemens; Soldermann, Nicolas; Hebach, Christina; Hollingworth, Gregory J.; Lewis, Ian; Matt, Anette von; Smith, Alexander B; Wolf, Romain M.; Wilcken, Rainer; Haasen, Dorothea; Burkhart, Christoph; Zécri, Frédéric

doi:10.1016/j.bmcl.2016.10.069

Cited by 19 publications

(22 citation statements)

References 33 publications

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“…7A), consistent with previous results in primary murine microglia (Low et al, 2014). A different potent PI3K␦ inhibitor generated by Novartis, a methoxypyridyl substituted quinazoline analogous to Leniolisib (CDZ173), hereafter named "compound 12" (Hoegenauer et al, 2016), induced similar effects to CAL-101 in primary microglia (Fig. 7B), without affecting the cells' metabolic rate (Fig.…”

Section: Pi3k␦ Deficiency Attenuates A␤ Levels and Plaque Burden In Asupporting

confidence: 89%

p110δ PI3-Kinase Inhibition Perturbs APP and TNFα Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model

et al. 2019

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Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-␤ (A␤) peptide. Accumulation of A␤, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression being underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored. Here, we report that inactivation of the p110␦ isoform of phosphoinositide 3-kinase (PI3K) reduces anterograde axonal trafficking of APP in hippocampal neurons and dampens secretion of the inflammatory cytokine tumor necrosis factor-alpha by microglial cells in the familial AD APP swe /PS1 ⌬E9 (APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3K␦ (␦ D910A) had reduced A␤ peptides levels and plaques in the brain and an abrogated inflammatory response compared with APP/PS1 littermates. Mechanistic investigations reveal that PI3K␦ inhibition decreases the axonal transport of APP by eliciting the formation of highly elongated tubular-shaped APP-containing carriers, reducing the levels of secreted A␤ peptide. Importantly, APP/PS1/␦ D910A mice exhibited no spatial learning or memory deficits. Our data highlight inhibition of PI3K␦ as a new approach to protect against AD pathology due to its dual action of dampening microglial-dependent neuroinflammation and reducing plaque burden by inhibition of neuronal APP trafficking and processing.

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Section: Pi3k␦ Deficiency Attenuates A␤ Levels and Plaque Burden In Asupporting

confidence: 89%

p110δ PI3-Kinase Inhibition Perturbs APP and TNFα Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model

et al. 2019

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“…By rearranging fragments of known oncologic drugs, his team improved the selectivity and potency of the compound toward other PI3Ks. After co‐crystallization of this hit with the protein, they ran a SAR study to improve the safety profile and activity of the new lead …”

Section: Figurementioning

confidence: 99%

“…After co-crystallization of this hit with the protein, they ran aS AR www.chemmedchem.org study to improvet he safety profile and activity of the new lead. [19,20] The Immunooncologya nd Immunomodulation session comprised three talks on Monday.F irst, Dr.A nna Vulpetti (Novartis) presented the development of small-molecule inhibitors for factor D, an S1 serine protease involved in aw ide range of diversec linical disorders. Combining scaffolds from both fragment-based screening and structure-based protein design, her team obtained al igand capable of selectively binding to factor Dt hat has shown activity in the nanomolar range (K d : 0.006 mm)i nadirect binding assay using surface plasmon resonance spectroscopy.…”

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confidence: 99%

Frontiers in Medicinal Chemistry 2017 in Bern, Switzerland

et al. 2017

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Sharing capital ideas: The 2017 Frontiers in Medicinal Chemistry (FiMC) conference, organized jointly by the German Chemical Society, the German Pharmaceutical Society, and the Swiss Chemical Society, was held at the Department of Chemistry and Biochemistry of the University of Bern in February 2017. Herein we summarize the many conference highlights, and look forward to the next FiMC meeting, to be held in Jena (Germany) in March 2018.

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“…The PI3K family is subdivided into three classes, i.e., Class I, Class II, and Class III. The Class-I PI3K family catalyzes the phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2) to produce phosphatidyl-inositol(3,4,5)-trisphosphate (PIP3) [1][2]. PIP3 is a membrane-bound second messenger that activates downstream signaling pathways and crucial for cellular processes, such as proliferation, metabolism, and survival [3][4].…”

Section: ■ Introductionmentioning

confidence: 99%

Identification of Phosphatidylinositol 3-kinase δ (PI3Kδ) Inhibitor: Pharmacophore-based Virtual Screening and Molecular Dynamics Simulation

2020

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Phosphatidylinositol 3-kinase δ (PI3Kδ) is a validated drug target for the treatment of cancer. The present study aims to search for new inhibitors of PI3Kδ by employing pharmacophore modelling using LigandScout Advanced 4.3 software. The three hydrogen bond acceptors and two hydrophobic features were proposed as a pharmacophore model using LASW1976 structure. The model was then validated using the Area Under Curve (AUC) of Receiver Operating Characteristic (ROC) and GH score. It was used to screen new molecules in the ZINC database, which resulted in 599 hits. All 599 hits were then docked into PI3Kδ protein, and five best hits were submitted to 50 ns molecular dynamics simulations. Each hit complexed with PI3Kδ underwent minor conformational changes as indicated by the values of Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF). Furthermore, prediction of the binding free energy using Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) method showed that five hits, i.e., Lig25/ZINC253496376, Lig682/ZINC98047241, Lig449/ZINC85878047, Lig554/ZINC253389510, and Lig199/ZINC12638303, had lower binding energy compared to LASW1976. This result indicated their potentials as new inhibitors of PI3Kδ.

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Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties

Cited by 19 publications

References 33 publications

p110δ PI3-Kinase Inhibition Perturbs APP and TNFα Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model

p110δ PI3-Kinase Inhibition Perturbs APP and TNFα Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model

Frontiers in Medicinal Chemistry 2017 in Bern, Switzerland

Identification of Phosphatidylinositol 3-kinase δ (PI3Kδ) Inhibitor: Pharmacophore-based Virtual Screening and Molecular Dynamics Simulation

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