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(12) United States Patent (10) Patent No.: US 8,372,861 B2 Koong Et Al

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(12) United States Patent (10) Patent No.: US 8,372,861 B2 Koong Et Al USOO8372861 B2 (12) United States Patent (10) Patent No.: US 8,372,861 B2 Koong et al. (45) Date of Patent: Feb. 12, 2013 (54) INHIBITORS OF THE UNFOLDED PROTEIN 2003.0049701 A1 3/2003 Muraca RESPONSE AND METHODS FOR THEIR USE 2003/0224428 A1 12/2003 Ron et al. 2006,0041006 A1 2/2006 Ibrahim et al. (75) Inventors: Albert C. Koong, Los Altos, CA (US); 2006/0247320 A1 1 1/2006 Tagatet al. Douglas E. Feldman, Mountain View, FOREIGN PATENT DOCUMENTS CA (US) WO 2007101224 A2 9, 2007 (73) Assignee: The Board of Trustees of the Leland OTHER PUBLICATIONS Stanford Junior University, Palo Alto, Wolff, Manfred E. "Burger's Medicinal Chemistry, 5ed, Part I”, John CA (US) Wiley & Sons, 1995, pp.975-977.* Banker, G.S. et al., “Modern Pharmaceutics, 3ed...'. Marcel Dekker, (*) Notice: Subject to any disclaimer, the term of this New York, 1996, pp. 451 and 596.* patent is extended or adjusted under 35 Dorwald F. A. Side Reactions in Organic Synthesis, 2005, Wiley: U.S.C. 154(b) bV 1039 days. VCH. Weinheim pg. IX of Preface.* (b) by yS Bakhite et al. English abstract DN 133:309854 2000.* Perola, et al., “Successful Virtual Screening of a Chemical Database (21) Appl. No.: 12/280,793 for Farnesyltransferase Inhibitor Leads,” Jounal of Medicinal Chem istry, 2000, vol.43, No. 3, 401–408. (22) PCT Filed: Feb. 27, 2007 Iwawaki, et al., “A transgenic mouse model for monitoring endoplasmic reticulum stress.” Nature Medicine, Jan. 2004, vol. 10, (86). PCT No.: PCT/US2007/062917 No. 1,98-102. S371 (c)(1) Kaufman, “Orchestrating the unfolded protein response in health and 2). (4) Dat . 9, 2009 disease.” The Journal of Clinical Investigation, Nov. 2002, vol. 110, (2), (4) Date: Jan. 9, No. 10, 1389-1398. Zhang et al., “Signaling the Unfolded Protein Response from the (87) PCT Pub. No.: WO2007/101224 Endoplasmic Reticulum.” The Journal of Biological Chemistry, Jun. PCT Pub. Date: Sep. 7, 2007 18, 2004, vol. 279, No. 25, 25935-25938. e f 9 Garber, “Researchers Target Unfolded Protein Response in Cancer ous Tumor Growth.” Journal of the National Cancer Institute, Apr. 19. (65) Prior Publication Data 2006, vol. 98, No. 8, 512-514. US 2009/0312362 A1 Dec. 17, 2009 Feldman, et al., “The Unfolded Protein Response: A Novel Compo nent of the Hypoxic Stress Response in Tumors.” Mol Cancer Res, Related U.S. Application Data Nov. 2005, vol. 3, No. 11,597-605. Search Report and Written Opinion of the International Searching (60) Provisional application No. 60/777,458, filed on Feb. Authority, application No. PCT/US07/62917, mailed Aug. 14, 2008. 27, 2006. Search Report and Written Opinion of the International Searching Authority, application No. PCT/US07/62918, mailed Sep. 30, 2008. (51) Int. Cl. A6 IK3I/435 (2006.01) * cited by examiner CO7D 22/04 (2006.01) (52) U.S. Cl. ........................................ 514,299.546/112 Primary Examiner Rita Desai (58) Field of Classification Search .................. s46,112 (74) Attorney, Agent, or Firm – David J. Aston; Peters 514/229, 299 Verny, LLP See application file for complete search history. (57) ABSTRACT (56) References Cited Compounds that are inhibitors of the unfolded protein response and endonuclease IRE1 are provided, together with U.S. PATENT DOCUMENTS compositions comprising such compounds, and methods for 4,172,896 A 10, 1979 Uno et al. their use in the treatment of various disorders, such as cancer, 5,358,970 A 10/1994 Ruffet al. autoimmune disorders, and diabetes. Also provided are pack 5,427,798 A g 1995 E. t al. aged pharmaceuticals comprising these compositions. The 3:63 A sE. SE I. compositions may be administered in combination with 5,763,493 A 6/1998 Ruffetal. another therapeutic agent. 5,958,703 A 9, 1999 Dower et al. 6,110,973 A 8/2000 Young 18 Claims, 27 Drawing Sheets U.S. Patent Feb. 12, 2013 Sheet 1 of 27 US 8,372,861 B2 HYPOXA HF s GLYCOLYSIS, ANGIOGENESIS, Ero1, PD CELL MOTILITY, INVASION Ser/Thr H CYTOSOL RNASE/ HE Ser/Thr TRAF2 Rese KNSEE | 83 ASK UPR JNK1 TRANSCRIPTION PEOCASPASE-12 FACTORS CHAPERONES ER PROTEIN DEGRADATION ANGIOGENESIS APOPTOSIS REGULATION FIG. 1 U.S. Patent Feb. 12, 2013 Sheet 2 of 27 US 8,372,861 B2 lie ERHYPOXA STRESS S XBP-1 200 LUCIFERASE FRAME SHIFT HYPOXA REOXYGENATION O 8 24 ? 4. 8 HRS U.S. Patent Feb. 12, 2013 Sheet 3 of 27 US 8,372,861 B2 PRIMARY SCREEN #COMPOUNDS 66,000 SECONDARY SCREEN: C5OANDTOXCITY INHIBITOR ) CMV-LUCFERASE SELECT COMPOUNDS THAT SPECIFICALLYINHIBIT THE re. PATHWAY 58 (0.09%) OBTAIN COMPOUNDS FROMWENDOR ASSAY FOR INHIBITION OFire IXBP-1 FOLLOWING EXPOSURE 15 (0.02%) TO HYPOXA. SELECTMOST PROMISINGCOMPOUNDSFOR TUMOR STUDIES FIG. 3 U.S. Patent Feb. 12, 2013 Sheet 4 of 27 US 8,372,861 B2 COLUMN %INHIBITION FIG. 4 U.S. Patent Feb. 12, 2013 Sheet 5 of 27 US 8,372,861 B2 RESTATINS BLOCKSPLICE-ACTIVATION OFXBP-LUCIFERASE DURINGER STRESS OOOOO 90000+ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - we w w w x w w w w w w w w w w w w w w w w w w w w w w w w w w w we we w w w w w we we w w sex w w Me w w w w we s& sex & 8 as we as a was w w w y w P. pp. Pass p see P-38s we as as sess x-sea w w w w w we UNSTRESSED +Tm2 g/ml U.S. Patent Feb. 12, 2013 Sheet 6 of 27 US 8,372,861 B2 5XUPRE-LUCIFERASE 250 48 hrs HYPOXA 200 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - aso 150+------------------------------------------------ S. 9 a 5 100+------------------------------------------------ +1 MCOMPOUND 50 + - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - O NOCPD 0953 2437 3281 361 5116 6111 733 O222 140 2880 3456 3938 5500 6149 9255 FIG. 5B U.S. Patent Feb. 12, 2013 Sheet 7 of 27 US 8,372,861 B2 XBP-1 RT-PCRANALYSIS 24 HRSANOXA+/- COMPOUND o U.S. Patent Feb. 12, 2013 Sheet 8 of 27 US 8,372,861 B2 1.M.COMPOUND NORMOXA 48 HRS HYPOXA U.S. Patent Feb. 12, 2013 Sheet 9 of 27 US 8,372,861 B2 HYPOXA-SPECIFICCYTOTOXCITY OFIRE INHIBITORS HYPOXA 48 HRS t HT 1080 FIBROSARCOMACELLS FIG. 7A U.S. Patent Feb. 12, 2013 Sheet 10 of 27 US 8,372,861 B2 HYPOXA-SPECIFICCYTOTOXCITY OFIRE INHIBITORS MiaPACA 2 CELLS HYPOXA 48 HRS "...wow.* O824. 5500 2614 FIG. 7B U.S. Patent Feb. 12, 2013 Sheet 11 of 27 US 8,372,861 B2 COMPOUND ID: se 264 328 NORMOXA HYPOXA 48 HRS U.S. Patent Feb. 12, 2013 Sheet 12 of 27 US 8,372,861 B2 COMPOUND: . 2880 328 U.S. Patent Feb. 12, 2013 Sheet 13 Of 27 US 8,372,861 B2 CLICK iDEF20060104141849 WED,JANO4, 2006 14:19:19 OHRS FIG. 9A 500 4OO 3003 -200 CLICK HDEF2006010517287 WED,JANO5, 2006 17:28:46A 8 HRS FIG. 9B U.S. Patent Feb. 12, 2013 Sheet 14 of 27 US 8,372,861 B2 FRI, JANO6, 2006 30:28 24 HRS FIG. 9C CLICK HDEF2O06OO6 173434 FRI, JANO6, 20 O6 171735 3 8 HRS FIG. 9D U.S. Patent Feb. 12, 2013 Sheet 15 of 27 US 8,372,861 B2 + NOCOMPOUND A RESTATIN 1401 a RESTATIN 9337 x RESTATIN3611 A RESTATIN9389 DAYS AFTERTUMOR IMPLANTATION F.G. 10 U.S. Patent Feb. 12, 2013 Sheet 16 of 27 US 8,372,861 B2 REO SPLICE SITE HYPOXA RE10 ER STRESS 1 XBP.S 200 LUCFERASE FRAME SHIFT FIG 11A OXBP-LUCIFERASE CMV-LUCFERASE O RESTATIN 9389 CH3 FIG 11C U.S. Patent Feb. 12, 2013 Sheet 17 of 27 US 8,372,861 B2 XBP-LUCFERASE HYPOXA M " 3 RESTATIN - sw O 24 48 HRS F.G. 11D 5XUPRELUCIFERASE HYPOXA RESTATIN U.S. Patent Feb. 12, 2013 Sheet 18 of 27 US 8,372,861 B2 STRESS Tim - Tm RESTATIN XBP-1s actin GAPDH WB, HIF-10 WBXBP-1s WB: actin U.S. Patent Feb. 12, 2013 Sheet 19 of 27 US 8,372,861 B2 FIG. 12A 16 HRSPRETREAT VEHICLE RESTATIN Tm (HRS) O 0.5 2 O 0.5 2 F.G. 12B Tm 15 HR - TNF-0 - 9389 9337 611 3938 2880 WB, JNK F.G. 12C HIS6-1RE10-cyto LYSATE N2'pd FG, 12D U.S. Patent Feb. 12, 2013 Sheet 20 Of 27 US 8,372,861 B2 NO PROTEIN His6-1RE10-cyto TIME (MIN).0 60 120 0 60 120 IRESTATIN: - - - + - + - + 1 2 3 4 5 6 8 9 F.G. 12E 10 | IRESTATIN9389 O A VEHICLE g 80- xyy 60 Cld 2, 40 s 20 MINUTES FIG. 12F RNASe A RNAsin RESTATIN VEHICLE TMEMN); O' 15 O 15' 0 15 o . FIG. 12G U.S. Patent Feb. 12, 2013 Sheet 21 of 27 US 8,372,861 B2 WEHICLE RESTATIN kDa N 6 12 18 N. 6 12 18 HRSHYPOXIA WBATF6 WBCHOP 20 S ::$3:::::$::::::::::::$: WBactin 1 2 3 4. 1 2 3 4 5 6 7 8 WB:Caspase-3 F.G. 13A FIG. 13B H48 RESTATIN RESTATIN - + - + FIG. 13D U.S. Patent Feb. 12, 2013 Sheet 22 of 27 US 8,372,861 B2 TET-OFF FLAG-XBP-1s O WBFLAG RESTATIN F.G. 13F FIG. 13G H48 +dox -dox & t 8 + RESTATIN FIG. 13H U.S. Patent Feb. 12, 2013 Sheet 23 of 27 US 8,372,861 B2 HT1080 FIBROSARCOMA RPM 8226 MYELOMA {X VEHICLE A-25 MIRESTATIN 3-5 OUM RESTATIN U.S. Patent Feb. 12, 2013 Sheet 24 of 27 US 8,372,861 B2 2 5 RESTATIN 9389 20 50mg/kg oneouse 15 4 HRS O LEFTTUMOR:XBP-UC RIGHTTUMOR: CMV-UC FIG.
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