18 results on '"Meyerowitz JG"'
Search Results
2. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells
- Author
-
Lee, JK, Phillips, JW, Smith, BA, Park, JW, Stoyanova, T, McCaffrey, EF, Baertsch, R, Sokolov, A, Meyerowitz, JG, Mathis, C, Cheng, D, Stuart, JM, Shokat, KM, Gustafson, WC, Huang, J, and Witte, ON
- Subjects
Male ,Aging ,Cell Transformation ,Mice ,2.1 Biological and endogenous factors ,Exome ,Molecular Targeted Therapy ,Neoplasm Metastasis ,Aetiology ,Aurora Kinase A ,Cancer ,Tumor ,Prostate Cancer ,Azepines ,myc ,Neoplasm Proteins ,Neuroendocrine Tumors ,5.1 Pharmaceuticals ,Neoplastic Stem Cells ,Development of treatments and therapeutic interventions ,Biotechnology ,Urologic Diseases ,Recombinant Fusion Proteins ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Laser Capture Microdissection ,Adenocarcinoma ,SCID ,Cell Line ,Proto-Oncogene Proteins c-myc ,Transduction ,Genetic ,Animals ,Humans ,Neoplasm Invasiveness ,Oncology & Carcinogenesis ,Protein Kinase Inhibitors ,Neoplastic ,Phenylurea Compounds ,Neurosciences ,Prostatic Neoplasms ,Epithelial Cells ,Xenograft Model Antitumor Assays ,Enzyme Activation ,Pyrimidines ,Gene Expression Regulation ,Genes ,Inbred NOD ,Orchiectomy ,Proto-Oncogene Proteins c-akt - Abstract
© 2016 Elsevier Inc. MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.
- Published
- 2016
3. The prenatal origins of cancer
- Author
-
Marshall, GM, Carter, DR, Cheung, BB, Liu, T, Mateos, MK, Meyerowitz, JG, Weiss, WA, Marshall, GM, Carter, DR, Cheung, BB, Liu, T, Mateos, MK, Meyerowitz, JG, and Weiss, WA
- Abstract
The concept that some childhood malignancies arise from postnatally persistent embryonal cells has a long history. Recent research has strengthened the links between driver mutations and embryonal and early postnatal development. This evidence, coupled with much greater detail on the cell of origin and the initial steps in embryonal cancer initiation, has identified important therapeutic targets and provided renewed interest in strategies for the early detection and prevention of childhood cancer. © 2014 Macmillan Publishers Limited. All rights reserved.
- Published
- 2014
4. Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.
- Author
-
Burnett GL, Yang YC, Aggen JB, Pitzen J, Gliedt MK, Semko CM, Marquez A, Evans JW, Wang G, Won WS, Tomlinson ACA, Kiss G, Tzitzilonis C, Thottumkara AP, Cregg J, Mellem KT, Choi JS, Lee JC, Zhao Y, Lee BJ, Meyerowitz JG, Knox JE, Jiang J, Wang Z, Wildes D, Wang Z, Singh M, Smith JAM, and Gill AL
- Subjects
- Humans, Mechanistic Target of Rapamycin Complex 1, Proto-Oncogene Proteins p21(ras) metabolism, Cell Proliferation, TOR Serine-Threonine Kinases, Mechanistic Target of Rapamycin Complex 2, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors chemistry, Cell Line, Tumor, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS
G12C shows increased antitumor activity in a preclinical model of KRASG12C mutant NSCLC that exhibits resistance to KRASG12C inhibitor monotherapy.- Published
- 2023
- Full Text
- View/download PDF
5. Structure determination of inactive-state GPCRs with a universal nanobody.
- Author
-
Robertson MJ, Papasergi-Scott MM, He F, Seven AB, Meyerowitz JG, Panova O, Peroto MC, Che T, and Skiniotis G
- Subjects
- Cryoelectron Microscopy, Crystallography, X-Ray, Crystallization, Receptors, G-Protein-Coupled chemistry, Drug Discovery
- Abstract
Cryogenic electron microscopy (cryo-EM) has widened the field of structure-based drug discovery by allowing for routine determination of membrane protein structures previously intractable. Despite representing one of the largest classes of therapeutic targets, most inactive-state G protein-coupled receptors (GPCRs) have remained inaccessible for cryo-EM because their small size and membrane-embedded nature impedes projection alignment for high-resolution map reconstructions. Here we demonstrate that the same single-chain camelid antibody (nanobody) recognizing a grafted intracellular loop can be used to obtain cryo-EM structures of inactive-state GPCRs at resolutions comparable or better than those obtained by X-ray crystallography. Using this approach, we obtained structures of neurotensin 1 receptor bound to antagonist SR48692, μ-opioid receptor bound to alvimopan, apo somatostatin receptor 2 and histamine receptor 2 bound to famotidine. We expect this rapid, straightforward approach to facilitate the broad exploration of GPCR inactive states without the need for extensive engineering and crystallization., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2022
- Full Text
- View/download PDF
6. Author Correction: Plasticity in ligand recognition at somatostatin receptors.
- Author
-
Robertson MJ, Meyerowitz JG, Panova O, Borrelli K, and Skiniotis G
- Published
- 2022
- Full Text
- View/download PDF
7. Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19.
- Author
-
Feyaerts D, Hédou J, Gillard J, Chen H, Tsai ES, Peterson LS, Ando K, Manohar M, Do E, Dhondalay GKR, Fitzpatrick J, Artandi M, Chang I, Snow TT, Chinthrajah RS, Warren CM, Wittman R, Meyerowitz JG, Ganio EA, Stelzer IA, Han X, Verdonk F, Gaudillière DK, Mukherjee N, Tsai AS, Rumer KK, Jacobsen DR, Bjornson-Hooper ZB, Jiang S, Saavedra SF, Valdés Ferrer SI, Kelly JD, Furman D, Aghaeepour N, Angst MS, Boyd SD, Pinsky BA, Nolan GP, Nadeau KC, Gaudillière B, and McIlwain DR
- Subjects
- Humans, NF-kappa B metabolism, Proteomics, SARS-CoV-2, Signal Transduction, COVID-19
- Abstract
The biological determinants underlying the range of coronavirus 2019 (COVID-19) clinical manifestations are not fully understood. Here, over 1,400 plasma proteins and 2,600 single-cell immune features comprising cell phenotype, endogenous signaling activity, and signaling responses to inflammatory ligands are cross-sectionally assessed in peripheral blood from 97 patients with mild, moderate, and severe COVID-19 and 40 uninfected patients. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identify and independently validate a multi-variate model classifying COVID-19 severity (multi-class area under the curve [AUC]
training = 0.799, p = 4.2e-6; multi-class AUCvalidation = 0.773, p = 7.7e-6). Examination of informative model features reveals biological signatures of COVID-19 severity, including the dysregulation of JAK/STAT, MAPK/mTOR, and nuclear factor κB (NF-κB) immune signaling networks in addition to recapitulating known hallmarks of COVID-19. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for prevention and/or treatment of COVID-19 progression., Competing Interests: Declaration of interests S.D.B. has consulted for Regeneron, Sanofi, Novartis, and Janssen on topics unrelated to this study and owns stocks in AbCellera Biologics. The other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
8. The tethered peptide activation mechanism of adhesion GPCRs.
- Author
-
Barros-Álvarez X, Nwokonko RM, Vizurraga A, Matzov D, He F, Papasergi-Scott MM, Robertson MJ, Panova O, Yardeni EH, Seven AB, Kwarcinski FE, Su H, Peroto MC, Meyerowitz JG, Shalev-Benami M, Tall GG, and Skiniotis G
- Subjects
- Cell Adhesion, Cell Membrane metabolism, Cryoelectron Microscopy, Humans, Peptides chemistry, Protein Binding, Receptors, Peptide, Receptors, G-Protein-Coupled metabolism, Signal Transduction
- Abstract
Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell-cell and cell-extracellular matrix interactions
1 . Self cleavage within the aGPCR auto-proteolysis-inducing (GAIN) domain produces two protomers-N-terminal and C-terminal fragments-that remain non-covalently attached after receptors reach the cell surface1 . Upon dissociation of the N-terminal fragment, the C-terminus of the GAIN domain acts as a tethered agonist (TA) peptide to activate the seven-transmembrane domain with a mechanism that has been poorly understood2-5 . Here we provide cryo-electron microscopy snapshots of two distinct members of the aGPCR family, GPR56 (also known as ADGRG1) and latrophilin 3 (LPHN3 (also known as ADGRL3)). Low-resolution maps of the receptors in their N-terminal fragment-bound state indicate that the GAIN domain projects flexibly towards the extracellular space, keeping the encrypted TA peptide away from the seven-transmembrane domain. High-resolution structures of GPR56 and LPHN3 in their active, G-protein-coupled states, reveal that after dissociation of the extracellular region, the decrypted TA peptides engage the seven-transmembrane domain core with a notable conservation of interactions that also involve extracellular loop 2. TA binding stabilizes breaks in the middle of transmembrane helices 6 and 7 that facilitate aGPCR coupling and activation of heterotrimeric G proteins. Collectively, these results enable us to propose a general model for aGPCR activation., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
- Full Text
- View/download PDF
9. Plasticity in ligand recognition at somatostatin receptors.
- Author
-
Robertson MJ, Meyerowitz JG, Panova O, Borrelli K, and Skiniotis G
- Subjects
- Ligands, Receptors, Somatostatin metabolism
- Abstract
Somatostatin is a signaling peptide that plays a pivotal role in physiologic processes relating to metabolism and growth through its actions at somatostatin receptors (SSTRs). Members of the SSTR subfamily, particularly SSTR2, are key drug targets for neuroendocrine neoplasms, with synthetic peptide agonists currently in clinical use. Here, we show the cryogenic-electron microscopy structures of active-state SSTR2 in complex with heterotrimeric G
i3 and either the endogenous ligand SST14 or the FDA-approved drug octreotide. Complemented by biochemical assays and molecular dynamics simulations, these structures reveal key details of ligand recognition and receptor activation at SSTRs. We find that SSTR ligand recognition is highly diverse, as demonstrated by ligand-induced conformational changes in ECL2 and substantial sequence divergence across subtypes in extracellular regions. Despite this complexity, we rationalize several known sources of SSTR subtype selectivity and identify an additional interaction for specific binding. These results provide valuable insights for structure-based drug discovery at SSTRs., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2022
- Full Text
- View/download PDF
10. The oxytocin signaling complex reveals a molecular switch for cation dependence.
- Author
-
Meyerowitz JG, Robertson MJ, Barros-Álvarez X, Panova O, Nwokonko RM, Gao Y, and Skiniotis G
- Subjects
- Animals, Cations, Female, Pregnancy, Receptors, Oxytocin chemistry, Receptors, Oxytocin genetics, Receptors, Oxytocin metabolism, Receptors, Vasopressin chemistry, Signal Transduction, Magnesium, Oxytocin chemistry, Oxytocin metabolism
- Abstract
Oxytocin (OT) and vasopressin (AVP) are conserved peptide signaling hormones that are critical for diverse processes including osmotic homeostasis, reproduction, lactation and social interaction. OT acts through the oxytocin receptor (OTR), a magnesium-dependent G protein-coupled receptor that is a therapeutic target for treatment of postpartum hemorrhage, dysfunctional labor and autism. However, the molecular mechanisms that underlie OTR activation by OT and the dependence on magnesium remain unknown. Here we present the wild-type active-state structure of human OTR bound to OT and miniG
q/i determined by cryo-EM. The structure reveals a unique activation mechanism adopted by OTR involving both the formation of a Mg2+ coordination complex between OT and the receptor, and disruption of transmembrane helix 7 (TM7) by OT. Our functional assays demonstrate the role of TM7 disruption and provide the mechanism of full agonism by OT and partial agonism by OT analogs. Furthermore, we find that the identity of a single cation-coordinating residue across vasopressin family receptors determines whether the receptor is cation-dependent. Collectively, these results demonstrate how the Mg2+ -dependent OTR is activated by OT, provide essential information for structure-based drug discovery efforts and shed light on the molecular determinants of cation dependence of vasopressin family receptors throughout the animal kingdom., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2022
- Full Text
- View/download PDF
11. Drug discovery in the era of cryo-electron microscopy.
- Author
-
Robertson MJ, Meyerowitz JG, and Skiniotis G
- Subjects
- Crystallography, X-Ray, Cryoelectron Microscopy methods, Drug Discovery methods
- Abstract
Structure-based drug discovery (SBDD) is an indispensable approach for the design and optimization of new therapeutic agents. Here, we highlight the rapid progress that has turned cryo-electron microscopy (cryoEM) into an exceptional SBDD tool, and the wealth of new structural information it is providing for high-value pharmacological targets. We review key advantages of a technique that directly images vitrified biomolecules without the need for crystallization; both in terms of a broader array of systems that can be studied and the different forms of information it can provide, including heterogeneity and dynamics. We discuss near- and far-future developments, working in concert towards achieving the resolution and throughput necessary for cryoEM to make a widespread impact on the SBDD pipeline., Competing Interests: Declaration of interests The authors declare that they have no conflicts of interest with the content of this article., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
12. G-protein activation by a metabotropic glutamate receptor.
- Author
-
Seven AB, Barros-Álvarez X, de Lapeyrière M, Papasergi-Scott MM, Robertson MJ, Zhang C, Nwokonko RM, Gao Y, Meyerowitz JG, Rocher JP, Schelshorn D, Kobilka BK, Mathiesen JM, and Skiniotis G
- Subjects
- Cell Membrane chemistry, Cell Membrane metabolism, GTP-Binding Protein alpha Subunits, Gi-Go chemistry, GTP-Binding Protein alpha Subunits, Gi-Go metabolism, Heterotrimeric GTP-Binding Proteins chemistry, Humans, Models, Molecular, Protein Multimerization, Receptors, Metabotropic Glutamate chemistry, Heterotrimeric GTP-Binding Proteins metabolism, Receptors, Metabotropic Glutamate metabolism
- Abstract
Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism
1 . Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric Gi . Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6-TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound Gi can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6-TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2021
- Full Text
- View/download PDF
13. Asymmetric activation of the calcium-sensing receptor homodimer.
- Author
-
Gao Y, Robertson MJ, Rahman SN, Seven AB, Zhang C, Meyerowitz JG, Panova O, Hannan FM, Thakker RV, Bräuner-Osborne H, Mathiesen JM, and Skiniotis G
- Subjects
- Calcium chemistry, Humans, Models, Molecular, Peptides chemistry, Peptides metabolism, Protein Binding, Receptors, Calcium-Sensing ultrastructure, Substrate Specificity, Calcium metabolism, Cryoelectron Microscopy, Protein Multimerization, Receptors, Calcium-Sensing chemistry, Receptors, Calcium-Sensing metabolism
- Abstract
The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca
2+ , is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders1 . CaSR is a family C G-protein-coupled receptor2 that functions as an obligate homodimer, with each protomer composed of a Ca2+ -binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca2+ and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2021
- Full Text
- View/download PDF
14. Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19.
- Author
-
Feyaerts D, Hédou J, Gillard J, Chen H, Tsai ES, Peterson LS, Ando K, Manohar M, Do E, Dhondalay GKR, Fitzpatrick J, Artandi M, Chang I, Snow TT, Chinthrajah RS, Warren CM, Wittman R, Meyerowitz JG, Ganio EA, Stelzer IA, Han X, Verdonk F, Gaudillière DK, Mukherjee N, Tsai AS, Rumer KK, Jiang S, Valdés Ferrer SI, Kelly JD, Furman D, Aghaeepour N, Angst MS, Boyd SD, Pinsky BA, Nolan GP, Nadeau KC, Gaudillière B, and McIlwain DR
- Abstract
The biological determinants of the wide spectrum of COVID-19 clinical manifestations are not fully understood. Here, over 1400 plasma proteins and 2600 single-cell immune features comprising cell phenotype, basal signaling activity, and signaling responses to inflammatory ligands were assessed in peripheral blood from patients with mild, moderate, and severe COVID-19, at the time of diagnosis. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identified and independently validated a multivariate model classifying COVID-19 severity (multi-class AUCtraining = 0.799, p-value = 4.2e-6; multi-class AUCvalidation = 0.773, p-value = 7.7e-6). Features of this high-dimensional model recapitulated recent COVID-19 related observations of immune perturbations, and revealed novel biological signatures of severity, including the mobilization of elements of the renin-angiotensin system and primary hemostasis, as well as dysregulation of JAK/STAT, MAPK/mTOR, and NF-κB immune signaling networks. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for the prevention of COVID-19 progression.
- Published
- 2021
- Full Text
- View/download PDF
15. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells.
- Author
-
Lee JK, Phillips JW, Smith BA, Park JW, Stoyanova T, McCaffrey EF, Baertsch R, Sokolov A, Meyerowitz JG, Mathis C, Cheng D, Stuart JM, Shokat KM, Gustafson WC, Huang J, and Witte ON
- Subjects
- Adenocarcinoma pathology, Animals, Antineoplastic Agents therapeutic use, Aurora Kinase A antagonists & inhibitors, Aurora Kinase A physiology, Azepines therapeutic use, Cell Line, Tumor, Enzyme Activation, Epithelial Cells metabolism, Exome, Gene Expression Regulation, Neoplastic, Genes, myc, Humans, Laser Capture Microdissection, Male, Mice, Inbred NOD, Mice, SCID, Molecular Targeted Therapy, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Proteins genetics, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Neuroendocrine Tumors pathology, Orchiectomy, Phenylurea Compounds therapeutic use, Prostatic Neoplasms pathology, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-akt physiology, Pyrimidines therapeutic use, Recombinant Fusion Proteins metabolism, Transduction, Genetic, Xenograft Model Antitumor Assays, Adenocarcinoma genetics, Cell Transformation, Neoplastic genetics, Epithelial Cells pathology, Neoplasm Proteins physiology, Neuroendocrine Tumors genetics, Prostatic Neoplasms genetics, Proto-Oncogene Proteins c-myc physiology
- Abstract
MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
16. A new "angle" on kinase inhibitor design: Prioritizing amphosteric activity above kinase inhibition.
- Author
-
Meyerowitz JG, Weiss WA, and Gustafson WC
- Abstract
The MYCN oncoprotein has remained an elusive target for decades. We recently reported a new class of kinase inhibitors designed to disrupt the conformation of Aurora kinase A enough to block its kinase-independent interaction with MYCN, resulting in potent degradation of MYCN. These studies provide proof-of-principle for a new method of targeting enzyme activity-independent functions of kinases and other enzymes.
- Published
- 2015
- Full Text
- View/download PDF
17. Drugging MYCN through an allosteric transition in Aurora kinase A.
- Author
-
Gustafson WC, Meyerowitz JG, Nekritz EA, Chen J, Benes C, Charron E, Simonds EF, Seeger R, Matthay KK, Hertz NT, Eilers M, Shokat KM, and Weiss WA
- Subjects
- Allosteric Regulation, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Area Under Curve, Aurora Kinase A antagonists & inhibitors, Aurora Kinase A metabolism, Catalytic Domain, Cell Line, Tumor, Cell Survival drug effects, Crystallography, X-Ray, Humans, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Models, Molecular, N-Myc Proto-Oncogene Protein, Neuroblastoma pathology, Nuclear Proteins chemistry, Oncogene Proteins chemistry, Phenylurea Compounds chemistry, Phenylurea Compounds pharmacokinetics, Phosphorylation, Protein Processing, Post-Translational, Protein Structure, Secondary, Proteolysis, Pyrimidines chemistry, Pyrimidines pharmacokinetics, S Phase Cell Cycle Checkpoints drug effects, Structure-Activity Relationship, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Aurora Kinase A chemistry, Neuroblastoma drug therapy, Nuclear Proteins metabolism, Oncogene Proteins metabolism, Phenylurea Compounds pharmacology, Pyrimidines pharmacology
- Abstract
MYC proteins are major drivers of cancer yet are considered undruggable because their DNA binding domains are composed of two extended alpha helices with no apparent surfaces for small-molecule binding. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and drives the degradation of MYCN protein across MYCN-driven cancers. Comparison of cocrystal structures with structure-activity relationships across multiple inhibitors and chemotypes, coupled with mechanistic studies and biochemical assays, delineates an Aurora A conformation-specific effect on proteolytic degradation of MYCN, rather than simple nanomolar-level inhibition of Aurora A kinase activity., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
18. The prenatal origins of cancer.
- Author
-
Marshall GM, Carter DR, Cheung BB, Liu T, Mateos MK, Meyerowitz JG, and Weiss WA
- Subjects
- Animals, B-Lymphocytes physiology, Carcinogenesis genetics, Cerebellar Neoplasms pathology, Child, Down Syndrome etiology, Down Syndrome pathology, Embryo, Mammalian pathology, Female, Genomic Instability, Humans, Medulloblastoma pathology, Mutation, Myeloproliferative Disorders etiology, Myeloproliferative Disorders pathology, Neural Crest pathology, Neuroblastoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Pregnancy, Cerebellar Neoplasms etiology, Medulloblastoma etiology, Neuroblastoma etiology
- Abstract
The concept that some childhood malignancies arise from postnatally persistent embryonal cells has a long history. Recent research has strengthened the links between driver mutations and embryonal and early postnatal development. This evidence, coupled with much greater detail on the cell of origin and the initial steps in embryonal cancer initiation, has identified important therapeutic targets and provided renewed interest in strategies for the early detection and prevention of childhood cancer.
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.