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(12) Patent Application Publication (10) Pub. No.: US 2016/0235763 A1 Budunova Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0235763 A1 Budunova Et Al US 2016O235763A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0235763 A1 BudunOVa et al. (43) Pub. Date: Aug. 18, 2016 (54) USE OF REDD1 INHIBITORSTO Publication Classification DISSOCATE THERAPEUTIC AND ADVERSE ATROPHOGENCEFFECTS OF (51) Int. Cl. GLUCOCORTICOD RECEPTORAGONSTS A613 L/56 (2006.01) A613 L/713 (2006.01) (71) Applicant: Northwestern University, Evanston, IL A613 L/436 (2006.01) (US) (52) U.S. Cl. CPC ............... A61 K3I/56 (2013.01); A61 K3I/436 (72) Inventors: Irina Budunova, Chicago, IL (US); (2013.01); A61 K3I/713 (2013.01) Gleb Baida, Chicago, IL (US); Joel Dudley, Rye, NY (US) (57) ABSTRACT (73) Assignee: Northwestern University, Evanston, IL (US) Disclosed are methods and pharmaceutical compositions for treating diseases, disorders, and conditions associated with (21) Appl. No.: 15/046,075 glucocorticoid receptor (GR) expression and activity. The disclosed methods typically include administering to a (22) Filed: Feb. 17, 2016 patient in need thereofaglucocorticoid receptor (GR) agonist and administering to the patient in need thereof a REDD1 Related U.S. Application Data inhibitor that inhibits expression or activity of REDD1, (60) Provisional application No. 62/117,248, filed on Feb. wherein the REDD1 inhibitor is administered before, concur 17, 2015. rently with, or after the GRagonist is administered. Patent Application Publication Aug. 18, 2016 Sheet 1 of 17 US 2016/0235763 A1 Figre s: S. 48 :383.3 ge is: 8xx xx & s SS s sa a:23 8x3: & 25 88: c s S: 3 3 : 88 s : 3. s 3 : 3S s is $8 3S. .'ss& 3S citos. 8d.: Patent Application Publication Aug. 18, 2016 Sheet 2 of 17 US 2016/0235763 A1 Figure 2 A. s S$33-&Estigatya: ::cisestigatax :E::::::: 88:3E s S. 3:. .8. 23.8 Xxxxx e $38,3:388 Se:- E3: Mrs. 3 2 iss. -: : : 3: 33.8 Bex:s: & s: 3.2 s: 3. 83 SSS : 3& s-> & 8 & 88: 23: 3:38 Patent Application Publication Aug. 18, 2016 Sheet 3 of 17 US 2016/0235763 A1 Figare 3 i & E 3. asso's trichrie A. & s y s: s Ex. X 8 3 x A. & A. REDD: Ko wi. Red KO C :S s: 2Es36 3-8:EE-35 83:sss Patent Application Publication Aug. 18, 2016 Sheet 4 of 17 US 2016/0235763 A1 Figure- 4 A. g83 re s 28 sess: --- 38: 3. S : & is S. SS8 3 s 2s Š R : : y REE s: K. s:, REER3.3x 3:388. SR ss: . s SEE:- .. S& Patent Application Publication Aug. 18, 2016 Sheet 5 of 17 US 2016/0235763 A1 sgress 3.338 Patent Application Publication Aug. 18, 2016 Sheet 6 of 17 US 2016/0235763 A1 Figure 6 A 3E Ees 8::s &PR83, KEE -- 8 S332 sREE 8:2 SE Best retro: C823 w8. e. Er as as: SSE3. St S. 3. 8s. 8. Patent Application Publication Aug. 18, 2016 Sheet 7 of 17 US 2016/0235763 A1 §§§ Patent Application Publication Aug. 18, 2016 Sheet 8 of 17 US 2016/0235763 A1 Figure 8 3882 sh:3:33 8:8; {SR 3.68 SA-88: g882, sh&Eieixi 8 SA 8: A. Patent Application Publication Aug. 18, 2016 Sheet 9 of 17 US 2016/0235763 A1 Figare 9 siast-ter. A treater cratic FA treatist 8. RE: 3-88 -39 SA88 88: C 3 hr 3 hr 33r FA Ax2 x pri-miR-22 C-CR sort-ter. A treatreit croic. A treatient 2.5 3-8:008 t s 4. s . s .s C & 8 hr 24r E. Ax FA Fixa Patent Application Publication Aug. 18, 2016 Sheet 10 of 17 US 2016/0235763 A1 Figure 88x39 RECOKO Patent Application Publication Aug. 18, 2016 Sheet 11 of 17 US 2016/0235763 A1 Figare is A HaCa, Q-PCR NHEK, Q-PCR CER, Q-PCR 2.5 3. 2.5 3. : 8, 2.5 8, is s 2 1.5 s : 1.5 w w s c 8.5 3: 8.5 5 ().5 8 8 Rapa saa s Rapa: rur- or Rapa; FA as s FA as 's- FA: Patent Application Publication Aug. 18, 2016 Sheet 12 of 17 US 2016/0235763 A1 Figure 2 A Q-PCR, HaCa &PCR, CE S 25 & s 2 s s S 15 1.5 ar w 0.5 8.5 (S. 2: a a o s S.2 e. un- is FA: aa. e ae Sir FA als se a. ax 3 WB, HaCa WB, CER S. 2: - - - - OS2: re re. - - FA a- a. se FA na Yale aa. RE GAFO Patent Application Publication Aug. 18, 2016 Sheet 13 of 17 US 2016/0235763 A1 A. 32. 38& s gaR8, :288 Figtreics 3 as: 38: s: 38 38 & 8 20 i. 38 ii. 8 r: ax 8.333.8333:8& 88: F& Rxias Raatik s s 38. 8. s s : & s : is 4 : s:x 3 : 3. 8.- : x : 8 : & . sax------ 8 s 8.33: 3:3: A 8: Ras 83348;& 8 &E Se: 3. 3. ck & Raxa &axas: : E. Rasa: Rags.--& Patent Application Publication Aug. 18, 2016 Sheet 14 of 17 US 2016/0235763 A1 A {Q-PCR, HaCat -PCR. CEN Figtres s 4. 5 3 CCN & s re 0.5 s s , C SA Rapa Rapa--FA Cir FA Rapa Rapa-FA S C74 5. CC2 g 8, 3. & s c 0.5 i. t FA Rapa Rapa-FA t FA Raga Rapa-FA S aca c FA Rapa Rapa-FFA g FA *Rapa Rapa-FA Patent Application Publication Aug. 18, 2016 Sheet 15 of 17 US 2016/0235763 A1 ####*±•;$$~£~**** ~~ºdex;*·*~ **<,•edaš* 88 æa?ara; 3??z w Patent Application Publication Aug. 18, 2016 Sheet 16 of 17 US 2016/0235763 A1 Figare 6 C Effect of Rapamycine of croton W3 oiced ear edea c-R 3. t FA Rapa-FA Patent Application Publication Aug. 18, 2016 Sheet 17 of 17 US 2016/0235763 A1 US 2016/0235763 A1 Aug. 18, 2016 USE OF REDD1 INHIBITORSTO critical role in the activation of glucocorticoid-responsive DISSOCATE THERAPEUTIC AND ADVERSE genes by the glucocorticoid receptor (GR). Most importantly, ATROPHOGENCEFFECTS OF REDD1 knockout (KO) animals appear to be resistant to GLUCOCORTICOD RECEPTORAGONSTS glucocorticoid-induced skin atrophy, and the inventors iden tified the protection of epidermal stem cells as an underlying CROSS-REFERENCE TO RELATED PATENT mechanism for the anti-atrophogenic effect of REDD1. In APPLICATIONS contrast, REDD1 KO mice were as sensitive as wild-type 0001. This application claims the benefit of priority to mice to the anti-inflammatory effects of glucocorticoids. This U.S. Provisional Patent Application No. 62/117,248, filed on suggests that REDD1 dissociates the beneficial therapeutic Feb. 17, 2015, the content of which is incorporated herein by effects from adverse atrophogenic effects of glucocorticoids reference in its entirety. in skin. Using bioinformatics, the inventors compared their array of data with thousands of publicly available DNA STATEMENT REGARDING FEDERALLY arrays, and identified a shared REDD1-dependent molecular SPONSORED RESEARCH ORDEVELOPMENT mechanism underlying steroid-induced atrophy in epidermis, Subcutaneous fat, and muscle. The inventors also identified 0002 This invention was made with government support potential REDD1 inhibitors among FDA-approved com under grant number R01 CA118890 awarded by the National pounds. Collectively, the inventors’ findings: a) introduce the Institutes of Health. The government has certain rights in the concept of innovative safer therapies with glucocorticoids invention. using REDD1 inhibitors to reduce/alleviate glucocorticoid induced skin atrophy and glucocorticoid atrophogenic effects BACKGROUND in other tissues; and b) identify REDD1 inhibitors that may be 0003. The field of the invention relates to methods for used for such GR-targeted therapies. treating diseases and disorders associated with glucocorticoid 0007 Accordingly, disclosed are methods and pharma receptor (GR) activity. In particular, the field of the invention ceutical compositions for treating or preventing diseases, dis relates to methods for treating diseases and disorders associ orders, and conditions associated with glucocorticoid recep ated with GR activity by administering a GRagonist and an tor (GR) activities. The diseases, disorders and conditions inhibitor of the regulated in development and DNA damage treated or prevented by the methods disclosed herein typically response protein 1 (REDD1). are responsive to administration of a GR agonist, Such as 0004 Glucocorticoid hormones are a mainstay of therapy known glucocorticoids. of numerous hyperproliferative and inflammatory diseases 0008. In some embodiments, the disclosed methods including asthma, arthritis, psoriasis, dermatitis and others. include administering to a patient in need thereof a GRago They are also major component of chemotherapy of numer nistand administering to the patient in need thereofan inhibi ous blood cancers including acute childhood leukemia and tor of the regulated in development and DNA damage multiple myeloma. response protein 1 (REDD1). The REDD1 inhibitor may 0005. The biological effects of glucocorticoids are medi inhibit expression or activity of REDD1. The REDD1 inhibi ated by the glucocorticoid receptor (GR), which functions as tor may be administered before, concurrently with, or after a ligand-specific transcription factor. In non-activated cells, the GRagonist is administered. the GR resides in the cytoplasm in a complex with chaperone 0009. In some embodiments, the disclosed methods proteins. Upon activation by a GRagonist, the GRS dissociate include administering an effective amount of a REDD1 from the chaperones, form homo-dimers, and enter the inhibitor to a patient exhibiting GRagonist induced atropho nucleus where they interact with the regulatory sequences in genic effects and/or to a patient at risk for developing GR gene promoters. The GR regulates gene expression via (i) agonist induced atrophogenic effects. Atrophogenic effects DNA-dependent transactivation that requires GR may include but are not limited to epidermal atropy, epider homodimerization and binding of the GRhomodimer to gene mal hypoplasia, epidermal thinning, and/or depletion of the promoters, which is referred to as “GR-transactivation.” and interfollicular basal keratinocyte population.
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