Leon O. Murphy
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View article: Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes
Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes Open
The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought …
View article: Autophagy in the commercial arena: a conversation with Dr. Leon Murphy, Chief Scientific Officer at Casma therapeutics
Autophagy in the commercial arena: a conversation with Dr. Leon Murphy, Chief Scientific Officer at Casma therapeutics Open
As a maturing field that continues to provide fundamental insights into cell physiology, autophagy is also beginning to attract considerable interest from the biotechnology/pharmaceutical sector. For this Editor's corner, I thought it woul…
View article: Supplementary Material from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity
Supplementary Material from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity Open
Supplementary Material from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
View article: Supplementary Material from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity
Supplementary Material from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity Open
Supplementary Material from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
View article: Supplementary Fig from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity
Supplementary Fig from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity Open
Supplementary Fig from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
View article: Data from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity
Data from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity Open
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 …
View article: Data from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity
Data from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity Open
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 …
View article: Supplementary Fig from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity
Supplementary Fig from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity Open
Supplementary Fig from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
View article: A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages
A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages Open
Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves transformation of infected phagolysomes from a site of killing into a nutrient-rich replicative niche. Here we show that a terpe…
View article: GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis
GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis Open
Membrane conjugation of GABARAP sequesters the FLCN-FNIP complex to coordinate activation of MiT/TFE family transcription factors.
View article: The E3 Ligase MuRF1 Degrades Myosin Heavy Chain Protein in Dexamethasone-Treated Skeletal Muscle
The E3 Ligase MuRF1 Degrades Myosin Heavy Chain Protein in Dexamethasone-Treated Skeletal Muscle Open
Skeletal muscle atrophy occurs as a side effect of treatment with synthetic glucocorticoids such as dexamethasone (DEX) and is a hallmark of cachectic syndromes associated with increased cortisol levels. The E3 ubiquitin ligase (muscle RIN…
View article: GABARAP membrane conjugation sequesters the FLCN-FNIP tumor suppressor complex to activate TFEB and lysosomal biogenesis
GABARAP membrane conjugation sequesters the FLCN-FNIP tumor suppressor complex to activate TFEB and lysosomal biogenesis Open
Adaptive changes in lysosomal capacity are driven by the transcription factors TFEB and TFE3 in response to increased autophagic flux and endolysosomal stress, yet the molecular details of their activation are unclear. LC3 and GABARAP memb…
View article: An iron-dependent metabolic vulnerability underlies VPS34-dependence in RKO cancer cells
An iron-dependent metabolic vulnerability underlies VPS34-dependence in RKO cancer cells Open
VPS34 is a key regulator of endomembrane dynamics and cargo trafficking, and is essential in cultured cell lines and in mice. To better characterize the role of VPS34 in cell growth, we performed unbiased cell line profiling studies with t…
View article: Autophagy Assays for Biological Discovery and Therapeutic Development
Autophagy Assays for Biological Discovery and Therapeutic Development Open
Autophagy is a lysosome-dependent intracellular degradation system required for various physiological processes and can be dysregulated in human disease. To understand its biological significance and underlying mechanisms, measuring autoph…
View article: Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders
Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders Open
Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR…
View article: Targeting quiescent leukemic stem cells using second generation autophagy inhibitors
Targeting quiescent leukemic stem cells using second generation autophagy inhibitors Open
In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically appro…
View article: Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling
Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling Open
While the ability for humans to host a complex microbial ecosystem is an essential property of life, the mechanisms allowing for immune tolerance of such a large microbial load are not completely understood and are currently the focus of i…
View article: Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9
Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9 Open
Iron is vital for many homeostatic processes, and its liberation from ferritin nanocages occurs in the lysosome. Studies indicate that ferritin and its binding partner nuclear receptor coactivator-4 (NCOA4) are targeted to lysosomes by a f…
View article: Functional CRISPR screening identifies the ufmylation pathway as a regulator of SQSTM1/p62
Functional CRISPR screening identifies the ufmylation pathway as a regulator of SQSTM1/p62 Open
SQSTM1 is an adaptor protein that integrates multiple cellular signaling pathways and whose expression is tightly regulated at the transcriptional and post-translational level. Here, we describe a forward genetic screening paradigm exploit…
View article: Association of <i>MTOR</i> Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism
Association of <i>MTOR</i> Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism Open
In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be suff…