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WO 2015/119624 Al 13 August 2015 (13.08.2015) P O P C T

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WO 2015/119624 Al 13 August 2015 (13.08.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/119624 Al 13 August 2015 (13.08.2015) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/436 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, PCT/US2014/015387 MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (22) International Filing Date: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 7 February 2014 (07.02.2014) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (25) Filing Language: English ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (71) Applicant: THE REGENTS OF THE UNIVERSITY kind of regional protection available): ARIPO (BW, GH, OF MICHIGAN [US/US]; 1600 Huron Parkway, 2nd GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Floor, Ann Arbor, MI 48109 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventor: SALTIEL, Alan R.; 2002 Valleyview Dr., Ann EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, Arbor, Michigan 48105 (US). MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (74) Agent: STAPLE, David W.; Casimir Jones, S.C., 2275 KM, ML, MR, NE, SN, TD, TG). Deming Way, Suite 310, Middleton, Wisconsin 53562 (US). Published: (81) Designated States (unless otherwise indicated, for every — with international search report (Art. 21(3)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: COMBINATIONS OF ΙΚΚε/ΤΒΚΙ INHIBITORS WITH BETA ADRENERGIC AGONISTS OR SYMPATHETIC NERVOUS SYSTEM ACTIVATORS FIG, Control S O 2.50 i t 2.00 -50 ~ 1.00 - S 0.50 0.00 (57) Abstract: Provided herein are methods of treating obesity and obesity-related conditions comprising the administration of com binations of ΙΚΚε/ΤΒΚΙ inhibitors with beta adrenergic agonists or sympathetic nervous system activators, and pharmaceutical com positions comprising such combinations. Obesity generates a state of chronic, low-grade inflammation in liver and adipose tissue ac companied by macrophage infiltration and the local secretion of inflammatory cytokines and chemokines that attenuate insulin ac - tion. COMBINATIONS OF ΙΚΚε /ΤΒΚΙ INHIBITORS WITH BETA ADRENERGIC AGONISTS OR SYMPATHETIC NERVOUS SYSTEM ACTIVATORS STATEMENT REGARDING GOVERNMENT FUNDING This invention was made with government support under DK060591 awarded by the National Institutes of Health. The Government has certain rights in the invention. FIELD Provided herein are methods of treating obesity and obesity-related conditions comprising the administration of combinations of ΙΚΚε/ΤΒΚΙ inhibitors with beta adrenergic agonists or sympathetic nervous system activators, and pharmaceutical compositions comprising such combinations. BACKGROUND Obesity generates a state of chronic, low-grade inflammation in liver and adipose tissue accompanied by macrophage infiltration and the local secretion of inflammatory cytokines and chemokines that attenuate insulin action, resulting in insulin resistance and the subsequent development of Type 2 diabetes (Wellen and Hotamisligil, 2005; Hotamisligil, 2006; Lumeng et al, 2007; Shoelson et al, 2007; herein incorporated by reference in their entireties). Numerous studies indicate a strong correlation between inflammation and insulin resistance across several populations (Hotamisligil, 2006; herein incorporated by reference in its entirety). Moreover, genetic ablation or pharmacological inhibition of inflammatory pathways can dissociate obesity from insulin resistance (Hotamisligil, 2006; Shoelson et al, 2007; herein incorporated by reference in their entireties). The transcription factor NFKB and its inflammatory program play an important role in the development of insulin resistance in obese liver and adipose tissue (Yuan et al, 2001; Arkan et al., 2005; Wunderlich et al., 2008; Chiang et al., 2009; herein incorporated by reference in their entireties). NFKB is activated by the ΙκΒ kinase (IKK) family, which has four members: ΙΚΚα, ΙΚΚβ, ΙΚΚε, and TBK1 . ΙΚΚα and ΙΚΚβ act with the scaffolding partner NEMO to activate NFKB (Hacker and Karin, 2006; herein incorporated by reference in its entirety). Although pharmacologic inhibition or genetic ablation of ΙΚΚβ defined a role for this kinase in insulin resistance (Yuan et al., 2001; Arkan et al., 2005; herein incorporated by reference in their entireties), the roles of the noncanonical kinases ΙΚΚε and TBK1 are not certain. Obesity is a complex metabolic disorder that is caused by increased food intake and decreased expenditure of energy. Obesity also increases the risk of developing type 2 diabetes, heart disease, stroke, arthritis, and certain cancers. There is considerable evidence to suggest that adipose tissue becomes less sensitive to catecholamines such as adrenaline in states of obesity, and that this reduced sensitivity in turn reduces energy expenditure. However, the details of this process are not fully understood. SUMMARY Provided herein are methods of treating obesity and obesity-related conditions comprising the administration of combinations of ΙΚΚε/ΤΒΚΙ inhibitors with beta adrenergic agonists or sympathetic nervous system activators, and pharmaceutical compositions comprising such combinations. In some embodiments, the present invention provides methods of treating a subject having a condition associated with obesity, insulin resistance, or hepatic steatosis, comprising: administering to a subject having a condition associated with obesity, insulin resistance, or hepatic steatosis: (i) an ΙΚ ε and/or TBK1 inhibitor, and (ii) a beta adrenergic agonist or sympathetic nervous system activator. In some embodiments, administering causes a reduction of body fat in the subject. In some embodiments, the subject has or is at risk of experiencing obesity, diabetes, or insulin resistance. In some embodiments, diabetes is type II diabetes. In some embodiments, the treatment results in increased glucose metabolism, reduction in body fat, lack of increase in body fat, increased insulin receptor signaling, decreased level of insulin receptor phosphorylation, reduction in or prevention of chronic inflammation in the liver, reduction in or prevention of chronic inflammation in adipose tissue, reduction in or prevention of hepatic steatosis, promotion of metabolic energy expenditure, reduction in circulating free fatty acids, or reduction in cholesterol. In some embodiments, the subject has hepatic steatosis (fatty liver disease). In some embodiments, the subject has steatohepatitis. In some embodiments, the subject is overweight or obese. In some embodiments, the subject is human. In some embodiments, methods further comprises a step comprising testing the subject for a disease or condition selected from the group consisting of impaired insulin signaling, obesity, diabetes, insulin resistance, metabolic syndrome, hepatic steatosis, chronic liver inflammation, and chronic inflammation in adipose tissue. In some embodiments, method further comprises a step of assessing the effectiveness of treatment based upon said testing. In some embodiments, method further comprises adjusting the treatment based on said assessing. In some embodiments, adjusting the treatment comprises one or more of altering the dose of ΙΚ ε/ΤΒΚΙ inhibitor, switching to a different ΙΚ ε/ΤΒΚΙ inhibitor, altering the dose of beta adrenergic agonist or sympathetic nervous system activator, switching to a different beta adrenergic agonist or sympathetic nervous system activator, adding additional treatment. In some embodiments, a method comprises administering a ΙΚ ε and/or TBKl inhibitor and a beta adrenergic agonist or sympathetic nervous system activator that are co- formulated in a single pharmaceutical composition. In other embodiments, the ΙΚΚε and/or TBKl inhibitor, and the beta adrenergic agonist or sympathetic nervous system activator are separate pharmaceutical compositions and are co-administered (e.g., within 1 hour, within 20 minutes, within 15 minutes, within 5 minutes, within 1minute, simultaneously, etc.). In some embodiments, the present invention provides pharmaceutical compositions comprising: (i) an ΙΚΚε and/or TBKl inhibitor, and (ii) a beta adrenergic agonist or sympathetic nervous system activator. In some embodiments, the ΙΚΚε and/or TBKl inhibitor comprises a small molecule. In some embodiments, the ΙΚΚε and/or TBKl inhibitor comprises the structure of Formula I : wherein Ri is a hydrogen, alkyl, phenyl, carboxyl, hydroxyl, alkoxy, or amino group, which may be unsubstituted or substituted by one alkyl; m is 0, 1 or 2; and R2 is alkyl, alkoxy, halogen, nitro, hydroxy, carboxyl, butadienylene (-CH=CH-CH=CH-), which forms a benzene ring with any adjacent carbon atoms or amino group, which may be unsubstituted or substituted by at least one alkyl, and their physiologically acceptable salts. In some embodiments, the ΙΚΚε and/or TBKl inhibitor comprises amlexanox. In some embodiments, the beta adrenergic agonist or sympathetic nervous system activator comprises a small molecule. In some embodiments, the beta
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