PI3Ks—Drug Targets in Inflammation and Cancer

Wymann, Matthias P.

doi:10.1007/978-94-007-3012-0_5

Cited by 10 publications

(18 citation statements)

References 545 publications

(503 reference statements)

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“…These interact with dedicated phosphorylated tyrosine motifs on growth factor receptors or their substrates via two src-homology 2 (SH2) domains present in their tightly associated p85 regulatory subunits. The class IB PI3K γ operates downstream of GPCRs and is composed of a catalytic subunit p110 γ and an adapter subunit, which is either p84 or p101 4…”

Section: Introductionmentioning

confidence: 99%

5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

et al. 2017

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Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.

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Section: Introductionmentioning

confidence: 99%

5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

et al. 2017

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“…Class I PI3K, PI3Kδ mediates downstream signaling of growth factors, cytokines, and immune receptors such as B-cell, T-cell, and Toll-like receptors [ 64 ]. The targeting of upstream catalytic and regulatory subunits to prevent downstream signaling may promote TEX-mediated immune suppression.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Transcriptomes and Proteomes of Serum Exosomes from Marek’s Disease Virus-Vaccinated and Protected and Lymphoma-Bearing Chickens

Neerukonda

Tavlarides-Hontz

McCarthy

et al. 2019

Genes

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Marek’s disease virus (MDV) is the causative agent of Marek’s disease (MD), a complex pathology of chickens characterized by paralysis, immunosuppression, and T-cell lymphomagenesis. MD is controlled in poultry production via vaccines administered in ovo or at hatch, and these confer protection against lymphoma formation, but not superinfection by MDV field strains. Despite vaccine-induced humoral and cell-mediated immune responses, mechanisms eliciting systemic protection remain unclear. Here we report the contents of serum exosomes to assess their possible roles as indicators of systemic immunity, and alternatively, tumor formation. We examined the RNA and protein content of serum exosomes from CVI988 (Rispens)-vaccinated and protected chickens (VEX), and unvaccinated tumor-bearing chickens (TEX), via deep-sequencing and mass spectrometry, respectively. Bioinformatic analyses of microRNAs (miRNAs) and predicted miRNA targets indicated a greater abundance of tumor suppressor miRNAs in VEX compared to TEX. Conversely, oncomiRs originating from cellular (miRs 106a-363) and MDV miRNA clusters were more abundant in TEX compared to VEX. Most notably, mRNAs mapping to the entire MDV genome were identified in VEX, while mRNAs mapping to the repeats flanking the unique long (IRL/TRL) were identified in TEX. These data suggest that long-term systemic vaccine-induced immune responses may be mediated at the level of VEX which transfer viral mRNAs to antigen presenting cells systemically. Proteomic analyses of these exosomes suggested potential biomarkers for VEX and TEX. These data provide important putative insight into MDV-mediated immune suppression and vaccine responses, as well as potential serum biomarkers for MD protection and susceptibility.

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“…Chorein has previously been shown to interact with PI3K [1,2], which is known to participate in the regulation of degranulation in a wide variety of cells [32,33,34,35,36,37,38,39,40]. Possibly, chorein similarly modifies degranulation of those cells.…”

Section: Discussionmentioning

confidence: 99%

Chorein Sensitive Dopamine Release from Pheochromocytoma (PC12) Cells

Honisch¹,

Fehrenbacher

Lebedeva

et al. 2015

Neurosignals

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Background: Chorein, a protein supporting activation of phosphoinositide 3 kinase (PI3K), participates in the regulation of actin polymerization and cell survival. A loss of function mutation of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) leads to chorea-acanthocytosis (ChAc), a neurodegenerative disorder with simultaneous erythrocyte akanthocytosis. In blood platelets chorein deficiency has been shown to compromise expression of vesicle-associated membrane protein 8 (VAMP8) and thus degranulation. The present study explored whether chorein is similarly involved in VAMP8 expression and dopamine release of pheochromocytoma (PC12) cells. Methods: Chorein was down-regulated by silencing in PC12 cells. Transmission electron microscopy was employed to quantify the number of vesicles, RT-PCR to determine transcript levels, Western blotting to quantify protein expression and ELISA to determine dopamine release. Results: Chorein silencing significantly reduced the number of vesicles, VAMP8 transcript levels and VAMP8 protein abundance. Increase of extracellular K⁺ from 5 mM to 40 mM resulted in marked stimulation of dopamine release, an effect significantly blunted by chorein silencing. Conclusions: Chorein deficiency down-regulates VAMP8 expression, vesicle numbers and dopamine release in pheochromocytoma cells.

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PI3Ks—Drug Targets in Inflammation and Cancer

Cited by 10 publications

References 545 publications

5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

Comparison of the Transcriptomes and Proteomes of Serum Exosomes from Marek’s Disease Virus-Vaccinated and Protected and Lymphoma-Bearing Chickens

Chorein Sensitive Dopamine Release from Pheochromocytoma (PC12) Cells

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