DOCSLIB.ORG

Total Synthesis and Chemoproteomics Connect Curcusone Diterpenes with Oncogenic Protein BRAT1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Total Synthesis and Chemoproteomics Connect Curcusone Diterpenes with Oncogenic Protein BRAT1 Total Synthesis and Chemoproteomics Connect Curcusone Diterpenes with Oncogenic Protein BRAT1 Chengsen Cui1†, Brendan G. Dwyer2†, Chang Liu1, Daniel Abegg2, Zhongjian Cai1, Dominic Hoch2, Xianglin Yin1, Nan Qiu2, Jieqing Liu3, Alexander Adibekian2*, Mingji Dai1* 1Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States 2Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States 3School of Medicine, Huaqiao University, Quanzhou 362021, P. R. China Correspondence and requests for materials should be addressed to M. D. (email: [email protected]) and A. A. ([email protected]) †Contributed equally. Abstract: Natural products are an indispensable source of lifesaving medicine, but natural product-based drug discovery often suffers from scarce natural supply and unknown mode of action. The study and development of anticancer curcusone diterpenes fall into such a dilemma. Meanwhile, many biologically- validated disease targets are considered “undruggable” due to the lack of enzymatic activity and/or predicted small molecule binding sites. The oncogenic BRCA1-associated ATM activator 1 (BRAT1) belongs to such an “undruggable” category. Here, we report our synthetic and chemoproteomics studies of the curcusone diterpenes that culminate in an efficient total synthesis and the identification of BRAT1 as a cellular target. We demonstrate for the first time that BRAT1 can be inhibited by a small molecule (curcusone D), resulting in impaired DNA damage response, reduced cancer cell migration, potentiated activity of the DNA damaging drug etoposide, and other phenotypes similar to BRAT1 knockdown. 1 Natural products have been valuable sources and inspirations of lifesaving drug molecules1. Their accumulated evolutionary wisdom together with their structural novelty and diversity makes them unparalleled for novel therapeutic development. However, their natural scarcity, structural complexity, and unknown mode of action often hamper their further development in the drug discovery pipeline. Total synthesis is frequently employed to solve the material supply and chemical probe synthesis for comprehensive biological profiling and target identification2. Meanwhile, many biologically validated disease targets are considered as “undruggable” from a chemical standpoint due to the lack of enzymatic activity and/or small molecule binding sites3. The BRCA1-associated ATM activator 1 (BRAT1) protein has been validated as an oncogenic protein involved in various cancers but belongs to the “undruggable” category with no known small molecule inhibitors to date. Herein, we report a collaborative effort in the total synthesis and chemoproteomics profiling of curcusone natural products which reveals BRAT1 as a key cellular target and validated curcusone D as the first BRAT1 inhibitor. The curcusone diterpenes (Fig. 1A) were isolated from Jatropha curcas, a widely used ingredient in traditional remedies for a variety of ailments including cancer. Structurally, they share a characteristic [6-7-5] tricyclic skeleton with the daphnane and tigliane diterpenes4. Curcusones A-D (1a-d), isolated by Clardy and co-workers in 1986, were unambiguously identified as two epimeric pairs at the C2 position5. Since then, around thirty curcusone molecules have been isolated including curcusones F-J6, which lack the dienone moiety in the seven-membered ring. Structurally rearranged analogs like spirocurcasone (3) and dimeric analogs such as dimericursone A (2a) and dimericursone B (2b) were discovered recently7,8. Among them, 1a-1d exhibited low micromolar IC50 values against a broad spectrum of human cancer cell lines6. However, their mode of action remained unknown and no total syntheses of 1a-1d were reported prior to this study. 2 A Curcusone Natural Products 12 18 13 11 16 O H 14 O H O H O H O H 15 H 2 9 8 H 2 H H H H 1 Me HO Me Me Me Me Me 7 17 Me Me Me OH 19 Me 3 5 6 Me Me HO Me MeO Me MeO OH O 20 O O O O Me Curcusone A (1a: 2S) Curcusone C (1c: 2R) Curcusone B (1b: 2R) Curcusone D (1d: 2S) Curcusone E (1e) Curcusone F (1f) Curcusone G (1g) anti cancer cell proliferation and antimetastatic Me Me Me O Me O H H O O H O H H H O O H H Me H Me Me H Me Me Me Me O H H H Me Me Me Me O O O O H Me Me Me Me Me H O O Me Me Curcusone I (1i: 2S) Curcusone H (1h) Curcusone J (1j: 2R) Spirocurcasone (3) putative structures Dimericursone A (2a) Dimericursone B (2b) B Our Previous Total Syntheses of Curcusones I and J MeO C Me 2 MeO2C O H TBSO Me H H TBSO TBSO TBSO H OTBS C H H OTBS H Me Au(I) Me O O O O Diels-Alder Me Me O Me Me TBSO 4 HO 5 TBSO putative (±)-1i & 1j Au-catalyzed furan formation/furan-allene [4+3] 6 7 (21 steps) C Synthetic Studies toward the Curcusones by Stoltz et al. TBSO O 6 steps TBSO OTBS OTBS HO Me H Me Br 5 steps H H 8 Me 10 O DIBAL-H HO Me Me + O OH 2 steps O Me HO Me H Me Suzuki coupling Cope Br BPin 13 14 OH cyclopropanation 12 rearrangement o 9 11 PhH, 50 C 31% from 12 D Retrosynthetic Analysis O H O H O H O H Pd, CO O H 14 H R2 Me H Me H Me H Me 10 2 7 or O 9 8 H Me R1 6 RCM or Me Carbonylative X Me Y OTf O O Aldol Condensation O O Coupling Curcusones A-D 15 (Y = H or halide) 16 17 18 (1a-d) Claisen rearrangement biomimetic Diels-Alder- cheletropic elimination O HO O 14 14 RO O 8 + Dimericursone A (2a) Me Me Me 8 X X Dimericursone B (2b) (S)-(-)-perillaldehyde 21 20a (R = H) O ($1.1/g, Sigma-Aldrich) X = masked aldehyde 20b (R = Et) 19 Fig. 1. Curcusone Diterpenes. (A) Selected curcusone diterpenes and their analogs. (B) Our total synthesis of the putative structures of curcusones I and J. (C) Synthetic efforts toward the curcusones from the Stotlz group. (D) Our retrosynthetic analysis of curcusones A-D. 3 While the closely related daphnane and tigliane diterpenes have attracted a significant amount of synthetic interest9-13, the curcusone molecules have surprisingly received little attention despite their therapeutic potential. In 2017, we reported the first total syntheses of the putative structures of 1i and 1j in 21 steps (Fig. 1B), ultimately leading to the conclusion that the originally proposed structures of both 1i and 1j were incorrect14. Our synthesis involves a gold-catalyzed tandem furan formation and furan-allene [4+3] cycloaddition to build the 5,7-fused ring system with an oxa bridge and a Diels-Alder reaction to construct the 6-membered ring. In 2019, Stoltz and co-workers reported their studies toward synthesizing 1a-1d (Fig. 1C)15-17. Their approach features a divinylcyclopropane-cycloheptadiene rearrangement to forge the 7-membered ring and reached advanced intermediate 14 after 12 steps from 8. Total Synthesis and Probe Synthesis. Our ongoing interest in natural products that can covalently modify cellular proteins18 prompted us to continue pursuing the total synthesis and target identification of 1a-1d with an electrophilic cycloheptadienone moiety. This unique structural feature could allow them to form a covalent bond with nucleophilic residues of certain cellular proteins19. Previous cytotoxicity studies found that reduction and/or oxidation of the C6-C7 double bond greatly reduced their anticancer activity6. As such, an approach allowing variation of the C6 and C7 substituents would be highly desirable. We envisioned 15 as an advanced intermediate (Fig. 1D). α-Halogenation followed by two methylation reactions would lead to 1a and 1b, which could be oxidized to 1c and 1d via a-hydroxylation. A ring closing metathesis (RCM) or an intramolecular aldol condensation was planned to form the 7-membered dienone (16/17®15). Both 16 and 17 could be prepared from vinyl triflate 18 via Pd-catalyzed carbonylative cross couplings. At this stage, disconnection of the C9-C10 bond could break 18 into two simple pieces, but a direct intermolecular C-C bond formation to construct such a bond is challenging. Thus, we opted for a Claisen rearrangement to forge this C-C bond in a stereoselective manner and designed 19 with a masked aldehyde as the Claisen rearrangement precursor. 19 could be assembled from simple building blocks 20a/20b and 21. The latter could be derived from a cheap chiral pool molecule (S)-(−)-perillaldehyde 8. 4 OHC O OH OHC 1. TBSOTf, NEt3 2. NaBH4 HO 3. O CH2Cl2, 0 °C to r.t. EtOH/CH2Cl2 20a then HC(OEt)3 Me 0 °C to r.t. Me PPh3, DEAD, THF Me Me BF3•OEt2, 0 °C EtO OEt 73% over 2 steps EtO OEt 0 °C to 50 °C O EtO OEt 8 22 23 24 (S)-(-)-perillaldehyde no purification OEt FeCl3 4. DMF O 27 6. FeCl (2-MeTHF) H H 5. H 3 OEt H 140-150 °C O Li EtO OH TMSCl Me Me H Me H H 48% Me OEt TMEDA OEt toluene, r.t. O+Et over 2 steps EtO OEt O THF, -78 °C O 39% over 2 steps O OH 25 26 28 29 (X-ray) no purification H H O O O H O H 8. Pd(dppf)Cl2 FeCl3 7. I2, DMAP Me4Sn, CuI H Me H Me H Me H O Me OFeCl2 pyr./CH2Cl2 DMF, 60 °C Me r.t. I 45% over 2 steps O O O O 17 30 15 31 no purification O H O H O H O H 9. KHMDS, MeI 10. KHMDS H Me THF, -78 °C 2 H Me MoOPH 2 H Me 11.
Load more

Recommended publications
  • Identification and Characterization of TPRKB Dependency in TP53 Deficient Cancers
    Identification and Characterization of TPRKB Dependency in TP53 Deficient Cancers. by Kelly Kennaley A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular and Cellular Pathology) in the University of Michigan 2019 Doctoral Committee: Associate Professor Zaneta Nikolovska-Coleska, Co-Chair Adjunct Associate Professor Scott A. Tomlins, Co-Chair Associate Professor Eric R. Fearon Associate Professor Alexey I. Nesvizhskii Kelly R. Kennaley [email protected] ORCID iD: 0000-0003-2439-9020 © Kelly R. Kennaley 2019 Acknowledgements I have immeasurable gratitude for the unwavering support and guidance I received throughout my dissertation. First and foremost, I would like to thank my thesis advisor and mentor Dr. Scott Tomlins for entrusting me with a challenging, interesting, and impactful project. He taught me how to drive a project forward through set-backs, ask the important questions, and always consider the impact of my work. I’m truly appreciative for his commitment to ensuring that I would get the most from my graduate education. I am also grateful to the many members of the Tomlins lab that made it the supportive, collaborative, and educational environment that it was. I would like to give special thanks to those I’ve worked closely with on this project, particularly Dr. Moloy Goswami for his mentorship, Lei Lucy Wang, Dr. Sumin Han, and undergraduate students Bhavneet Singh, Travis Weiss, and Myles Barlow. I am also grateful for the support of my thesis committee, Dr. Eric Fearon, Dr. Alexey Nesvizhskii, and my co-mentor Dr. Zaneta Nikolovska-Coleska, who have offered guidance and critical evaluation since project inception.
    [Show full text]
  • Inner Retinal Dystrophy in a Patient with Biallelic Sequence Variants in BRAT1
    Ophthalmic Genetics ISSN: 1381-6810 (Print) 1744-5094 (Online) Journal homepage: http://www.tandfonline.com/loi/iopg20 Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1 Julius T. Oatts, Jacque L. Duncan, Creig S. Hoyt, Anne M. Slavotinek & Anthony T. Moore To cite this article: Julius T. Oatts, Jacque L. Duncan, Creig S. Hoyt, Anne M. Slavotinek & Anthony T. Moore (2017) Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1, Ophthalmic Genetics, 38:6, 559-561, DOI: 10.1080/13816810.2017.1290118 To link to this article: https://doi.org/10.1080/13816810.2017.1290118 Published online: 02 Mar 2017. Submit your article to this journal Article views: 155 View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iopg20 OPHTHALMIC GENETICS 2017, VOL. 38, NO. 6, 559–561 http://dx.doi.org/10.1080/13816810.2017.1290118 CASE REPORT Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1 Julius T. Oattsa, Jacque L. Duncana, Creig S. Hoyta, Anne M. Slavotinekb, and Anthony T. Moorea,c,d aDepartment of Ophthalmology, University of California, San Francisco, San Francisco, California, USA; bDepartment of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, California, USA; cUCL Institute of Ophthalmology, University College London, London, UK; dInherited Eye Disease and Medical Retina Service, Moorfields Eye Hospital, London, UK ABSTRACT ARTICLE HISTORY Background: Mutations in the BRCA1-associated protein required for the ataxia telangiectasia mutated Received 17 October 2016 (ATM) activation-1 (BRAT1) gene cause lethal neonatal rigidity and multifocal seizure syndrome char- Revised 18 December 2016 acterized by rigidity and intractable seizures and a milder phenotype with intellectual disability, seizures, Accepted 29 January 2017 nonprogressive cerebellar ataxia or dyspraxia, and cerebellar atrophy.
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]
  • Whole Exome Sequencing in Families at High Risk for Hodgkin Lymphoma: Identification of a Predisposing Mutation in the KDR Gene
    Hodgkin Lymphoma SUPPLEMENTARY APPENDIX Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene Melissa Rotunno, 1 Mary L. McMaster, 1 Joseph Boland, 2 Sara Bass, 2 Xijun Zhang, 2 Laurie Burdett, 2 Belynda Hicks, 2 Sarangan Ravichandran, 3 Brian T. Luke, 3 Meredith Yeager, 2 Laura Fontaine, 4 Paula L. Hyland, 1 Alisa M. Goldstein, 1 NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, Stephen J. Chanock, 5 Neil E. Caporaso, 1 Margaret A. Tucker, 6 and Lynn R. Goldin 1 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 2Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 3Ad - vanced Biomedical Computing Center, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Frederick, MD; 4Westat, Inc., Rockville MD; 5Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; and 6Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA ©2016 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2015.135475 Received: August 19, 2015. Accepted: January 7, 2016. Pre-published: June 13, 2016. Correspondence: [email protected] Supplemental Author Information: NCI DCEG Cancer Sequencing Working Group: Mark H. Greene, Allan Hildesheim, Nan Hu, Maria Theresa Landi, Jennifer Loud, Phuong Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Anand Pathak, Douglas R. Stewart, Philip R. Taylor, Geoffrey S. Tobias, Xiaohong R. Yang, Guoqin Yu NCI DCEG Cancer Genomics Research Laboratory: Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Amy A.
    [Show full text]
  • Revostmm Vol 10-4-2018 Ingles Maquetaciûn 1
    108 ORIGINALS / Rev Osteoporos Metab Miner. 2018;10(4):108-18 Roca-Ayats N1, Falcó-Mascaró M1, García-Giralt N2, Cozar M1, Abril JF3, Quesada-Gómez JM4, Prieto-Alhambra D5,6, Nogués X2, Mellibovsky L2, Díez-Pérez A2, Grinberg D1, Balcells S1 1 Departamento de Genética, Microbiología y Estadística - Facultad de Biología - Universidad de Barcelona - Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) - Instituto de Salud Carlos III (ISCIII) - Instituto de Biomedicina de la Universidad de Barcelona (IBUB) - Instituto de Investigación Sant Joan de Déu (IRSJD) - Barcelona (España) 2 Unidad de Investigación en Fisiopatología Ósea y Articular (URFOA); Instituto Hospital del Mar de Investigaciones Médicas (IMIM) - Parque de Salud Mar - Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES); Instituto de Salud Carlos III (ISCIII) - Barcelona (España) 3 Departamento de Genética, Microbiología y Estadística; Facultad de Biología; Universidad de Barcelona - Instituto de Biomedicina de la Universidad de Barcelona (IBUB) - Barcelona (España) 4 Unidad de Metabolismo Mineral; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC); Hospital Universitario Reina Sofía - Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES); Instituto de Salud Carlos III (ISCIII) - Córdoba (España) 5 Grupo de Investigación en Enfermedades Prevalentes del Aparato Locomotor (GREMPAL) - Instituto de Investigación en Atención Primaria (IDIAP) Jordi Gol - Centro de Investigación
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Noncoding Rnas As Novel Pancreatic Cancer Targets
    NONCODING RNAS AS NOVEL PANCREATIC CANCER TARGETS by Amy Makler A Thesis Submitted to the Faculty of The Charles E. Schmidt College of Science In Partial Fulfillment of the Requirements for the Degree of Master of Science Florida Atlantic University Boca Raton, FL August 2018 Copyright 2018 by Amy Makler ii ACKNOWLEDGEMENTS I would first like to thank Dr. Narayanan for his continuous support, constant encouragement, and his gentle, but sometimes critical, guidance throughout the past two years of my master’s education. His faith in my abilities and his belief in my future success ensured I continue down this path of research. Working in Dr. Narayanan’s lab has truly been an unforgettable experience as well as a critical step in my future endeavors. I would also like to extend my gratitude to my committee members, Dr. Binninger and Dr. Jia, for their support and suggestions regarding my thesis. Their recommendations added a fresh perspective that enriched our initial hypothesis. They have been indispensable as members of my committee, and I thank them for their contributions. My parents have been integral to my successes in life and their support throughout my education has been crucial. They taught me to push through difficulties and encouraged me to pursue my interests. Thank you, mom and dad! I would like to thank my boyfriend, Joshua Disatham, for his assistance in ensuring my writing maintained a logical progression and flow as well as his unwavering support. He was my rock when the stress grew unbearable and his encouraging words kept me pushing along.
    [Show full text]
  • IDH1R132H Acts As a Tumor Suppressor in Glioma Via Epigenetic Upregulation of the DNA Damage Response
    bioRxiv preprint doi: https://doi.org/10.1101/389817; this version posted August 10, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. IDH1R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response Authors: Felipe J. Núñez1, 2, Flor M. Mendez2, Padma Kadiyala1, 2, Mahmoud S. Alghamri1, 2, Masha G. Savelieff1, 2, ‡, Carl Koschmann3, Anda-Alexandra Calinescu1, Neha Kamran1, 2, Rohin Patel1, Stephen Carney1, Marissa Z. Guo1, Maria B. Garcia-Fabiani1, 2, Santiago Haase1, 2, Marta Edwards1, 2, Mats Ljungman4, 5, Tingting Qin6, Maureen A. Sartor6, Rebecca Tagett6, Sriram Venneti7, Jacqueline Brosnan-Cashman8, Alan Meeker8, Vera Gorbunova9, Lili Zhao10, Daniel M. Kremer11,12, Li Zhang13, Costas A. Lyssiotis11,13,14, Lindsey Jones15, Cameron J. Herting16,17, James L. Ross16,18, Dolores Hambardzumyan16, Shawn Hervey-Jumper1, †, Maria E. Figueroa7, 11, Pedro R. Lowenstein1, 2, *, Maria G. Castro1, 2, 19,* . Affiliations: 1Departments of Neurosurgery 2Department of Cell and Developmental Biology 3Department of Pediatrics 4 Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA 5Department of Environmental Health Science, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA. 6Department of Computational Medicine and Bioinformatics, University of Michigan,
    [Show full text]
  • Downloaded from Bioscientifica.Com at 09/28/2021 09:08:00AM Via Free Access
    245 E L Woodward et al. Genetic changes in anaplastic 24:5 209–220 Research thyroid cancer Genomic complexity and targeted genes in anaplastic thyroid cancer cell lines Eleanor L Woodward1, Andrea Biloglav1, Naveen Ravi1, Minjun Yang1, Lars Ekblad2, Johan Wennerberg3 and Kajsa Paulsson1 1Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden Correspondence 2Division of Oncology and Pathology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden should be addressed 3Division of Otorhinolaryngology/Head and Neck Surgery, Clinical Sciences, Lund University and Skåne to K Paulsson University Hospital, Lund, Sweden Email [email protected] Abstract Anaplastic thyroid cancer (ATC) is a highly malignant disease with a very short median Key Words survival time. Few studies have addressed the underlying somatic mutations, and the f thyroid genomic landscape of ATC thus remains largely unknown. In the present study, we f molecular genetics have ascertained copy number aberrations, gene fusions, gene expression patterns, f gene expression and mutations in early-passage cells from ten newly established ATC cell lines using single nucleotide polymorphism (SNP) array analysis, RNA sequencing and whole exome sequencing. The ATC cell line genomes were highly complex and displayed signs of replicative stress and genomic instability, including massive aneuploidy and frequent Endocrine-Related Cancer Endocrine-Related breakpoints in the centromeric regions and in fragile sites. Loss of heterozygosity involving whole chromosomes was common, but there were no signs of previous near- haploidisation events or chromothripsis. A total of 21 fusion genes were detected, including six predicted in-frame fusions; none were recurrent.
    [Show full text]
  • C6cc08797c1.Pdf
    Electronic Supplementary Material (ESI) for Chemical Communications. This journal is © The Royal Society of Chemistry 2017 Supplementary Information for Competition-based, quantitative chemical proteomics in breast cancer cells identifies new target profiles for sulforaphane James A. Clulow,a,‡ Elisabeth M. Storck,a,‡ Thomas Lanyon-Hogg,a,‡ Karunakaran A. Kalesh,a Lyn Jonesb and Edward W. Tatea,* a Department of Chemistry, Imperial College London, London, UK, SW7 2AZ b Worldwide Medicinal Chemistry, Pfizer, 200 Cambridge Park Drive, MA 02140, USA ‡ Authors share equal contribution * corresponding author, email: [email protected] Table of Contents 1 Supporting Figures..........................................................................................................................3 2 Supporting Tables.........................................................................................................................17 2.1 Supporting Table S1. Incorporation validation for the R10K8 label in the 'spike-in' SILAC proteome of the MCF7 cell line........................................................................................................17 2.2 Supporting Table S2. Incorporation validation for the R10K8 label in the 'spike-in' SILAC proteome of the MDA-MB-231 cell line ...........................................................................................17 2.3 Supporting Table S3. High- and medium- confidence targets of sulforaphane in the MCF7 cell line..............................................................................................................................................17
    [Show full text]
  • Treatment of Epileptic Encephalopathies
    Treatment of epileptic encephalopathies Simona Balestrini, MD,a,b Sanjay M Sisodiya, PhD, FRCP.a aNIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, and Epilepsy Society, Chalfont-St- Peter, Bucks, United Kingdom; bNeuroscience Department, Polytechnic University of Marche, Ancona, Italy. Corresponding author: Simona Balestrini Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK +44 20 3448 8612 (telephone) +44 20 3448 8615 (fax) [email protected] Running title: ‘Treatment of epileptic encephalopathies’ 1 Abstract Background. Epileptic encephalopathies represent the most severe epilepsies, with onset in infancy and childhood and seizures continuing in adulthood in most cases. New genetic causes are being identified at a rapid rate. Treatment is challenging and the overall outcome remains poor. Available targeted treatments, based on the precision medicine approach, are currently few. Objective. To provide an overview of the treatment of epileptic encephalopathies with known genetic determinants, including established treatment, anecdotal reports of specific treatment, and potential tailored precision medicine strategies. Method. Genes known to be associated to epileptic encephalopathy were selected. Genes where the association was uncertain or with no reports of details on treatment, were not included. Although some of the genes included are associated with multiple epilepsy phenotypes or other organ involvement, we have mainly focused on the epileptic encephalopathies and their antiepileptic treatments. Results. Most epileptic encephalopathies show genotypic and phenotypic heterogeneity. The treatment of seizures is difficult in most cases. The available evidence may provide some guidance for treatment: for example, ACTH seems to be effective in controlling infantile spams in a number of genetic epileptic encephalopathies.
    [Show full text]
  • Mutations in BRAT1 Cause Autosomal Recessive Progressive Encephalopathy: Report of a Spanish Patient
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Eur J Paediatr Manuscript Author Neurol. Author Manuscript Author manuscript; available in PMC 2016 August 10. Published in final edited form as: Eur J Paediatr Neurol. 2016 May ; 20(3): 421–425. doi:10.1016/j.ejpn.2016.02.009. Mutations in BRAT1 cause autosomal recessive progressive encephalopathy: Report of a Spanish patient Alberto Fernández-Jáena,*, Sara Álvarezb, Eui Young Soc, Toru Ouchic, Mar Jiménez de la Peñad, Anna Duate, Daniel Martín Fernández-Mayoralasa, Ana Laura Fernández-Perronea, Jacobo Albertf, and Beatriz Calleja-Pérezg aDepartment of Pediatric Neurology, Hospital Universitario Quirón, Madrid, Spain bGenomics and Medicine, NIMGenetics, Madrid, Spain cDepartment of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA dNeuro-Radiology Unit, Magnetic Resonance Unit, Hospital Universitario Quirón, Madrid, Spain ePediatric Neurology Unit, Hospital Universitario Niño Jesús, Madrid, Spain fDepartment of Biological and Health Psychology, Faculty of Psychology, Universidad Autónoma de Madrid, Spain gPediatric Primary Care, C. S. Doctor Cirajas, Madrid, Spain Abstract We describe a 4-year-old male child born to non-consanguineous Spanish parents with progressive encephalopathy (PE), microcephaly, and hypertonia. Whole exome sequencing revealed compound heterozygous BRAT1 mutations [c.1564G > A (p.Glu522Lys) and c.638dup (p.Val214Glyfs*189)]. Homozygous and compound heterozygous BRAT1 mutations have been described in patients with lethal neonatal rigidity and multifocal seizure syndrome (MIM# 614498). The seven previously described patients suffered from uncontrolled seizures, and all of those patients died in their first months of life. BRAT1 acts as a regulator of cellular proliferation and migration and is required for mitochondrial function.
    [Show full text]