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).