Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy <i>in Vivo</i>

Honda, Ayako; Harrington, Edmund; Cornella-Taracido, Ivan; Furet, Pascal; Knapp, Mark; Glick, Meir; Triantafellow, Ellen; Dowdle, William E.; Wiedershain, Dmitri; Maniara, Wieslawa; Moore, Christine; Finan, Peter M.; Hamann, Lawrence G.; Firestone, Brant; Murphy, Leon O.; Keaney, Erin P.

doi:10.1021/acsmedchemlett.5b00335

Cited by 47 publications

(53 citation statements)

References 14 publications

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“…To examine the role of Vps34 activity, we used PIK-III, a potent chemical inhibitor of Vps34 that has high selectivity for Vps34 over other kinases (Dowdle et al, 2014;Honda et al, 2015). PIK-III application produced a pronounced redistribution of the 2xFYVE probe from endosomes to the cytoplasm ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibitors. PIK-III was synthesized according to the published protocol (Honda et al, 2015). The commercial sources of other inhibitors used in this study were as follows: WM (Sigma-Aldrich, St. Louis, MO); VPS34-IN1 (1-((2-((2-chloropyridin-4-yl)amino)-49-(cyclopropylmethyl)-[4,59-bipyrimidin]-29-yl)amino)-2-methylpropan-2-ol; MedKoo Biosciences, Chapel Hill, NC); SAR405 ((8S)-9-[(5-chloropyridin-3-yl)methyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(trifluoromethyl)-7,8dihydro-6H-pyrimido[1,2-a]pyrimidin-4-one; ApexBio, Houston, TX); GDC-0941 (4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl) methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine; Selleck Chemicals, Houston, TX); and YM201636 (YM201636, 6-amino-N-[3-(4-morpholin-4-ylpyrido[2,3]furo[2,4-b]pyrimidin-2-yl)phenyl]pyridine-3-carboxamide; Cayman Chemical, Ann Arbor, MI).…”

Section: Methodsmentioning

confidence: 99%

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Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling

et al. 2016

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G protein-coupled receptors (GPCRs), the largest family of signaling receptors, are critically regulated by endosomal trafficking, suggesting that endosomes might provide new strategies for manipulating GPCR signaling. Here we test this hypothesis by focusing on class III phosphatidylinositol 3-kinase (Vps34), which is an essential regulator of endosomal trafficking. We verify that Vps34 is required for recycling of the β2-adrenoceptor (β2AR), a prototypical GPCR, and then investigate the effects of Vps34 inhibition on the canonical cAMP response elicited by β2AR activation. Vps34 inhibition impairs the ability of cells to recover this response after prolonged activation, which is in accord with the established role of recycling in GPCR resensitization. In addition, Vps34 inhibition also attenuates the short-term cAMP response, and its effect begins several minutes after initial agonist application. These results establish Vps34 as an essential determinant of both short-term and long-term canonical GPCR signaling, and support the potential utility of the endosomal system as a druggable target for signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling

et al. 2016

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“…This explains the relative Vps34 specificity of the widely-used 3-methyladenine compound, which fits in this small pocket, unlike most class I PI3K inhibitors which are too bulky 200 . However, 3-methyladenine is not selective for Vps34, and highly-selective Vps34 inhibitors have now been developed [201][202][203][204][205][206] . These have been used to confirm the role of Vps34 in autophagy and vesicular trafficking, to identify putative autophagy substrates and autophagy cargo receptors 202 and a possible involvement of Vps34 in the regulation of signalling 201,207,208 .…”

Section: Commented [Bv28]mentioning

confidence: 99%

PI3K isoforms in cell signalling and vesicle trafficking

Bilanges

Posor

Vanhaesebroeck

2019

Nat Rev Mol Cell Biol

372

364

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Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3-phosphoinositide lipids which directly activate signal transduction pathways. In addition to being frequently genetically-activated in cancer, similar mutations in class I PI3Ks have now also been found in a human non-malignant overgrowth syndrome and a primary immune disorder which predisposes to lymphoma. The class II and III PI3Ks are regulators of membrane traffic along the endocytic route, in endosomal recycling and autophagy, with an indirect impact on cell signalling. Here we summarize current knowledge on the different PI3K classes and isoforms, focusing on recently uncovered biological functions and the mechanisms by which these kinases are stimulated. Areas covered include emerging evidence for isoform-specific regulation and function of Akt family members, potential non-cytotoxic actions of PI3K inhibitors in cancer and regulation of mTORC1 by class II and III PI3Ks. A deeper insight into the PI3K isoforms will undoubtedly continue to contribute to a better understanding of fundamental cell biological processes, and ultimately, in human disease. The cDNA cloning of the first catalytic subunit of a PI3K (p110, Ref. 1) in 1992 revealed close sequence similarity to the Saccharomyces cerevisiae Vps34 gene product, which was soon thereafter documented to possess PI3K activity in that it could convert phosphatidylinositol (PI) to its 3phosphorylated PI(3)P derivative 2. Subsequent bioinformatic and molecular biology approaches based on sequence homology of the kinase domain of these enzymes allowed the isolation of multiple PI3K genes from a range of organisms, with the Waterfield group proposing the now generally-accepted classification of the isoforms of PI3K 3-6. The main role of Vps34 in yeast in regulating the transport of proteins to the lysosome-like vacuole 7 indicates that regulation of vesicular traffic is the most ancient function of 3-phosphoinositides, with a role in signalling being a later addition in eukaryotic evolution 8. Genetic and pharmacological approaches have now uncovered the broad functions of the different PI3K isoforms, some of which are targets of the first approved PI3K inhibitors for the treatment of human cancer. The challenges faced in effectively targeting PI3K in disease have illustrated that much remains to be learned about PI3K biology. In this review, we summarize key recent insights into PI3K signalling and cell biology in mammals, for example, newly discovered human syndromes, resulting from constitutive activation of class I PI3Ks leading to tissue overgrowth 9 or immune deregulation 10, 11. Despite having been discovered over two decades ago 12, 13 , the class II PI3Ks remain the most enigmatic PI3K subfamily. Recent studies have started to uncover mechanisms by which these PI3Ks are regulated and how t...

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“…Results using PIK‐III demonstrate that in vitro treatment of CML CD34 + cells with this compound reduces the number of cells with capacity to engraft and leads to an almost complete elimination of engrafted primitive Philadelphia positive cells when combined with TKI . Although the chemical properties of PIK‐III are not suitable for in vivo studies, new derivatives have already been developed with oral bioavailability and remain to be tested in CML models .…”

Section: Targeting Therapy‐resistant CML Cells With Second‐generationmentioning

confidence: 99%

Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

2018

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Despite the development of selective BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) transforming the management of chronic myeloid leukaemia (CML), therapy-resistant leukaemic stem cells (LSCs) persist after TKI treatment and present an obstacle to a CML cure. Recently, we and others have made significant contributions to the field by unravelling survival dependencies in LSCs to work towards the goal of eradicating LSCs in CML patients. In this review, we describe these findings focusing on autophagy and mitochondrial metabolism, which have recently been uncovered as two essential processes for LSCs quiescence and survival respectively. In addition, we discuss the therapeutic potential of autophagy and mitochondrial metabolism inhibition as a strategy to eliminate CML cells in patients where the resistance to TKI is driven by BCR-ABL-independent mechanism(s).

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Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy in Vivo

Cited by 47 publications

References 14 publications

Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling

Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling

PI3K isoforms in cell signalling and vesicle trafficking

Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

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