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(12) Patent Application Publication (10) Pub. No.: US 2017/0042898A1 Berenson Et Al

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US 20170042898A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0042898A1 Berenson et al. (43) Pub. Date: Feb. 16, 2017 (54) METHODS AND COMPOSITIONS FOR Publication Classification TREATINGVIRAL OR VIRALLY-INDUCED (51) Int. Cl. CONDITIONS A63L/506 (2006.01) A6IR 9/00 (2006.01) (71) Applicants: HEMAQUEST A638/12 (2006.01) PHARMACEUTICALS, INC., San A6II 3/19 (2006.01) Diego, CA (US); TRUSTEES OF A6II 3/18 (2006.01) BOSTON UNIVERSITY, Boston, MA A6II 3/167 (2006.01) (US) A63L/4045 (2006.01) (72) Inventors: Ronald J. Berenson, Mercer Island, A6II 3/165. (2006.01) WA (US); Douglas V. Faller, Weston, A638/15 (2006.01) A6II 3/4402 (2006.01) MA (US) A6II 3/522 (2006.01) (73) Assignees: HEMAQUEST A6II 3/473 (2006.01) PHARMACEUTICALS, INC., San (52) U.S. Cl. Diego, CA (US); TRUSTEES OF CPC ........... A61 K3I/506 (2013.01); A61 K3I/522 BOSTON UNIVERSITY, Boston, MA (2013.01); A61K 9/0053 (2013.01); A61 K (US) 38/12 (2013.01); A61K 31/19 (2013.01); A61 K 3 1/473 (2013.01); A61K 31/167 (2013.01); (21) Appl. No.: 15/335,776 A61K 31/4045 (2013.01); A61K 3 1/165 (2013.01); A61K 38/15 (2013.01); A61 K (22) Filed: Oct. 27, 2016 3I/4402 (2013.01); A61K 31/18 (2013.01) Related U.S. Application Data (63) Continuation of application No. 14/728,592, filed on (57) ABSTRACT Jun. 2, 2015, now abandoned, which is a continuation of application No. 13/912,637, filed on Jun. 7, 2013, Provided are methods and compositions for the prevention now abandoned, which is a continuation of applica and/or treatment of viral conditions, virally-induced condi tion No. 13/046,555, filed on Mar. 11, 2011, now tions and inflammatory conditions. The methods can com abandoned. prise administering to a Subject a viral inducing agent with (60) Provisional application No. 61/430.931, filed on Jan. an antiviral agent, and optionally an additional agent. The 7, 2011, provisional application No. 61/313,052, filed viral inducing agent can be a HDAC inhibitor administered on Mar. 11, 2010. orally. Patent Application Publication Feb. 16, 2017 Sheet 1 of 21 US 2017/0042898A1 F.G. 1A FIG. 1B Patent Application Publication Feb. 16, 2017 Sheet 2 of 21 US 2017/0042898A1 12 8- xxxx xx t - i. w 3s s. :x s x GC Concertationsi s W 8. 8 :- 2 -- ---- assa &aasaxx-xx-xxxx -- acces:-- ---- &xas. i. e. wasy a k e - 3 x Patent Application Publication Feb. 16, 2017 Sheet 3 of 21 US 2017/0042898A1 F.G. 2C N 3. treated Drug only Cy Cy FIG. 2D 8 . 8x 3 2. ss t; P05 x x x s x e x 5 w: & s C. POV only fixi:3+Cy Patent Application Publication Feb. 16, 2017 Sheet 4 of 21 US 2017/0042898A1 FIG. 3A 8 Mock 10 mM 2.5 mM 50mM sia: a. ^i: Drug E. Drug-GCV 8. 8 ick I Drug Drug-GCV Patent Application Publication Feb. 16, 2017 Sheet 5 of 21 US 2017/0042898A1 2. c. -- - - - - - - Untreated 1mMValproic 2mM valproic 1mMNaB cit Acid Patent Application Publication Feb. 16, 2017 Sheet 6 of 21 US 2017/0042898A1 FIG. 4A 1. 8. f 600 3500 3400 3 - 17, ... 27% "*8...a3. Si said. Drug Only Drug-GCV 3. x s: x. x Untreated Scriptaid500 nM Scriptaic Scriptaic2u M. Patent Application Publication Feb. 16, 2017 Sheet 7 of 21 US 2017/0042898A1 F.G. 5A Saves X. ro- syssessesssssssss 5. SA-A. SAA SAA Drug Only Drug-GCW Patent Application Publication Feb. 16, 2017 Sheet 8 of 21 US 2017/0042898A1 *s 8: : x E3 E3 s: s w- trait 8.x wo. Dug Only Drugi-GCV Patent Application Publication Feb. 16, 2017. Sheet 9 of 21 US 2017/0042898A1 Patent Application Publication Feb. 16, 2017. Sheet 10 of 21 US 2017/0042898A1 xxx orro st-r- ssssssssssssssss s xx w w; treat: Oxanatin Oxantiatin Oxanatin a. S; Without GCV Patent Application Publication Feb. 16, 2017. Sheet 11 of 21 US 2017/0042898A1 r o 150 s: & 100 * - 5% :::::::: treated Apicidin Acid s without GCV ity Patent Application Publication Feb. 16, 2017. Sheet 13 of 21 US 2017/0042898A1 FG 1 OC 28 Y-8s: 2 ww --- 8. & as & s s s x: s : x: x x: Drug Only it 8 Patent Application Publication Feb. 16, 2017. Sheet 14 of 21 US 2017/0042898A1 Patent Application Publication Feb. 16, 2017. Sheet 15 of 21 US 2017/0042898A1 No. Patent Application Publication Feb. 16, 2017. Sheet 16 of 21 US 2017/0042898A1 F.G. 12A it. Of it (Cy Li C2 ***************************************************** Drug Ony C. Patent Application Publication Feb. 16, 2017. Sheet 17 of 21 US 2017/0042898A1 F.G. 12C §@º (nooreo at:~)pºleºnun c)ejwºdzo-decz „………………………No.Wº?º?-gºc? Drug Only Cf F.G. 12D Drug Only is {f Patent Application Publication Feb. 16, 2017. Sheet 18 of 21 US 2017/0042898A1 F.G. 12E 2s - Dug Oriy 3 Of F.G. 12F seºrºco• Patent Application Publication Feb. 16, 2017. Sheet 20 of 21 US 2017/0042898A1 F.G. 14 8. : Patent Application Publication Feb. 16, 2017. Sheet 21 of 21 US 2017/0042898A1 US 2017/0042898 A1 Feb. 16, 2017 METHODS AND COMPOSITIONS FOR SUMMARY OF THE INVENTION TREATINGVIRAL OR VIRALLY-INDUCED 0006. In one aspect, a method for treating and/or pre CONDITIONS venting a viral condition, a virally-induced condition, or an inflammatory condition comprising administering a histone CROSS-REFERENCE TO RELATED deacetylase inhibitor (HDAC inhibitor) and an antiviral APPLICATIONS agent wherein the HDAC inhibitor is a pyrimidine 0001. This application is a continuation application of hydroxamic acid derivative is provided. co-pending U.S. patent application Ser. No. 14/728,592 filed 0007. In another aspect, a method for treating and/or Jun. 2, 2015, which is a continuation application of U.S. preventing a viral or virally-induced condition is provided patent application Ser. No. 13/912,637 filed Jun. 7, 2013, comprising administering a HDAC inhibitor and an antiviral which is a continuation application of U.S. patent applica agent wherein the viral or virally-induced condition is tion Ser. No. 13/046,555 filed on Mar. 11, 2011, which caused by a DNA virus and the HDAC inhibitor is admin claims the benefit under 35 U.S.C. 119(e) of U.S. Provi istered at dose of less than 2 mg/kg per dose. sional Application No. 61/430,931 filed on Jan. 7, 2011, and 0008. In yet another aspect, a method for treating and/or U.S. Provisional Application No. 61/313,052 filed on Mar. preventing a viral condition, a virally-induced condition, or 11, 2010, the contents of each of which are incorporated an inflammatory condition is provided comprising adminis herein by reference in their entireties. tering a HDAC inhibitor and an antiviral agent wherein the MW of the HDAC inhibitor is greater than 275 g/mol. SEQUENCE LISTING 0009. In another aspect, a method for treating and/or preventing a viral condition or a virally-induced condition is 0002 The instant application contains a Sequence Listing provided, comprising administering a HDAC inhibitor which has been submitted in ASCII format via EFS-Web and wherein the HDAC inhibitor is a pyrimidine hydroxamic is hereby incorporated by reference in its entirety. Said acid derivative. ASCII copy, created on Oct. 26, 2016, is named 701586 0010. In another aspect, a composition comprising a (i) 070083. SL.txt and is 1,296 bytes in size. HDAC inhibitor and (ii) an antiviral agent is provided, wherein the HDAC inhibitor is a pyrimidine hydroxamic BACKGROUND OF THE INVENTION acid derivative. 0011 Provided herein, in one aspect, is a method for 0003. Many patients can have latent infections in which treating and/or preventing a viral or virally-induced condi a virus is present but is not expressing viral proteins such as tion comprising administering a HDAC inhibitor and an viral thymidine kinase or protein kinase, the target for antiviral agent wherein the viral or virally-induced condition common anti-viral drugs such as acyclovir and ganciclovir. is caused by a DNA virus and the HDAC inhibitor is A viral inducing drug such as a histone deacetylase inhibitor administered at dose of less than 2 mg/kg per dose. In some (HDAC inhibitor HDACi) can be used to re-induce the embodiments, the HDAC inhibitor is Vorinostat/suberoyl expression of viral thymidine kinase or protein kinase in anilide hydroxamic acid, JNJ-26481585 (N-hydroxy-2-(4- viral infected cells in the subject; the subject can then be ((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)piperi treatment with antiviral drugs to eliminate latent viral infec din-1-yl)pyrimidine-5-carboxamide), R306465/JNJ tions. As EBV and/or other latent viral infections can be 1624 11.99 (N-hydroxy-5-(4-(naphthalen-2-ylsulfonyl) associated with a variety of conditions, many of which are piperazin-1-yl)pyrimidine-2-carboxamide), CHR-3996 (2- inflammatory conditions, such as lymphomas, autoimmune (6-(6-Fluoroquinolin-2-yl)methylamino-3-azabicyclo conditions, allergic conditions, eliminating the latent virus 3.1.0 hex-3-yl)-N-hydroxypyrimidine-5-carboxamide), with this therapy can be used to prevent or treat such Belinostat/PXD101, Panobinostat/LBH-589, trichostatin conditions. A/TSA (7-4-(dimethylamino)phenyl-N-hydroxy-4,6-dim 0004 EBV can induce autoimmune conditions through a ethyl-7-oxohepta-2,4-dienamide), ITF2357, CBHA, Givi number of potential mechanisms, e.g.: 1) activating B cells nostat/ITF2357, romidepsin (IstodaxTM), PCI-24781, depsi to produce auto-antibodies, 2) turning on T cells that attack peptide (FR901228 or FK228), butyrate, phenylbutyrate, host tissue, 3) molecular mimicry in which EBV antigens valproic acid, AN-9, CI-994, Entinostat/MS-275, SNDX cross react with host antigens such that autoimmune condi 275, mocetinostat/MGCD0103 (N-(2-aminophenyl)-4-((4- tion results when T cells or antibodies reactive with these pyridin-3-ylpyrimidin-2-ylamino)methyl)benzamide), antigens cross react with host antigens causing damage to m-carboxycinnamic acid, bishydroxamic acid, Suberic bis host tissues, 4) EBV infected B cells produce cytokines hydroxamic acid, oxamflatin, ABHA, SB-55629, pyroxam which turn on other elements of the immune system and ide, propenamides, aroyl pyrrolyl hydroxamides, and increase inflammation which can also exacerbate autoim LAQ824 (((E)-N-hydroxy-3-4-2-hydroxyethyl-2-(1H mune condition, 5) EBV infected B or T cells can become indol-3-yl)ethylaminomethylphenylprop-2-enamide).
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    MOLECULAR IDENTIFICATION AND GENETIC CHARACTERIZATION OF CETACEAN HERPESVIRUSES AND PORPOISE MORBILLIVIRUS By KARA ANN SMOLAREK BENSON A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2005 Copyright 2005 by Kara Ann Smolarek Benson I dedicate this to my best friend and husband, Brock, who has always believed in me. ACKNOWLEDGMENTS First and foremost I thank my mentor, Dr. Carlos Romero, who once told me that love is fleeting but herpes is forever. He welcomed me into his lab with very little experience and I have learned so much from him over the past few years. Without his excellent guidance, this project would not have been possible. I thank my parents, Dave and Judy Smolarek, for their continual love and support. They taught me the importance of hard work and a great education, and always believed that I would be successful in life. I would like to thank Dr. Tom Barrett for the wonderful opportunity to study porpoise morbillivirus in his laboratory at the Institute for Animal Health in England, and Dr. Romero for making the trip possible. I especially thank Dr. Ashley Banyard for helping me accomplish all the objectives of the project, and all the wonderful people at the IAH for making a Yankee feel right at home in the UK. I thank Alexa Bracht and Rebecca Woodruff who have been with me in Dr. Romero’s lab since the beginning. Their continuous friendship and encouragement have kept me sane even in the most hectic of times.
  • Hr23b Expression Is a Potential Predictive Biomarker for HDAC Inhibitor Treatment in Mesenchymal Tumours and Is Associated with Response to Vorinostat

    Hr23b Expression Is a Potential Predictive Biomarker for HDAC Inhibitor Treatment in Mesenchymal Tumours and Is Associated with Response to Vorinostat

    The Journal of Pathology: Clinical Research J Path: Clin Res April 2016; 2: 59–71 Original Article Published online 23 December 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/cjp2.35 HR23b expression is a potential predictive biomarker for HDAC inhibitor treatment in mesenchymal tumours and is associated with response to vorinostat Michaela Angelika Ihle,1 Sabine Merkelbach-Bruse,1 Wolfgang Hartmann,1,2 Sebastian Bauer,3 Nancy Ratner,4 Hiroshi Sonobe,5 Jun Nishio,6 Olle Larsson,7 Pierre A˚ man,8 Florence Pedeutour,9 Takahiro Taguchi,10 Eva Wardelmann,1,2 Reinhard Buettner1 and Hans-Ulrich Schildhaus1,11* 1 Institute of Pathology, University Hospital Cologne, Cologne, Germany 2 Gerhard Domagk Institute of Pathology, University Hospital M€unster, M€unster, Germany 3 Sarcoma Center, West German Cancer Center, University of Essen, Essen, Germany 4 US Department of Pediatrics, Cincinnati Children’s Hospital Medical Centre, Cincinnati, OH, USA 5 Department of Laboratory Medicine, Chugoku Central Hospital, Fukuyama, Hiroshima, Japan 6 Faculty of Medicine, Department of Orthopaedic Surgery, Fukuoka University, Fukuoka, Japan 7 Department of Oncology and Pathology, The Karolinska Institute, Stockholm, Sweden 8 Sahlgrenska Cancer Centre, University of Gothenburg, Gothenburg, Sweden 9 Faculty of Medicine, Laboratory of Genetics of Solid Tumours, Institute for Research on Cancer and Aging, Nice, France 10 Division of Human Health & Medical Science, Graduate School of Kuroshio Science, Kochi University Nankoku, Kochi, Japan 11 Institute of Pathology, University Hospital G€ottingen, G€ottingen, Germany *Correspondence to: Hans-Ulrich Schildhaus,Institute of Pathology,University Hospital G€ottingen,Robert-Koch-Strasse40,D-37075G€ottingen, Germany.e-mail: [email protected] Abstract Histone deacetylases (HDAC) are key players in epigenetic regulation of gene expression and HDAC inhibitor (HDACi) treatment seems to be a promising anticancer therapy in many human tumours, including soft tissue sar- comas.