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(12) Patent Application Publication (10) Pub. No.: US 2015/0157584A1 Guan Et Al US 2015O157584A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0157584A1 Guan et al. (43) Pub. Date: Jun. 11, 2015 (54) INHIBITORS OF HIPPO-YAP SIGNALING Publication Classification PATHWAY (51) Int. Cl. (71) Applicants: The Regents of the University of A613 L/15 (2006.01) O - O A613 L/44 (2006.01) California, Oakland, CA (US); The J. A 6LX3L/277 (2006.01) David Gladstone Institutes, San A613 L/45 (2006.015 Francisco, CA (US) A613 L/437 (2006.01) A 6LX39/395 (2006.01) (72) Inventors: Kun-Liang Guan, San Diego, CA (US); A613 L/522 (2006.01) Faxing Yu, San Diego, CA (US); Sheng A63/66 (2006.01) Ding, San Diego, CA (US) A638/48 (2006.01) A638/26 (2006.01) (73) Assignees: The J. David Gladstone Institutes, San A63L/38 (2006.01) Francisco, CA (US); The Regents of the A613 L/4453 (2006.01) University of California, Oakland, CA A613 L/405 (2006.01) US s s A613 L/404 (2006.01) (US) (52) U.S. Cl. CPC ............. A6 IK3 L/15 (2013.01); A61 K31/4015 (21) Appl. No.: 14/406,749 (2013.01); A61 K3I/44 (2013.01); A61 K 1-1. 3I/277 (2013.01); A61 K3I/451 (2013.01); (22) PCT Filed: May 31, 2013 A6 IK3I/437 (2013.01); A61 K3I/404 (2013.01); A61 K3I/522 (2013.01); A61 K (86). PCT No.: PCT/US2013/043752 3 1/661 (2013.01); A61 K38/4833 (2013.01): S371 (c)(1), A61K 38/26 (2013.01); A61 K3I/138 (2) Date: Dec. 9, 2014 (2013.01); A61 K3I/4453 (2013.01); A61 K 39/39558 (2013.01) (57) ABSTRACT Related U.S. Application Data This invention provides methods of preventing, reducing, (60) Provisional application No. 61/658,796, filed on Jun. delaying or inhibiting the proliferation, growth, migration 12, 2012, provisional application No. 61/658,084, and/or metastasis of cancer by administering an effective filed on Jun. 11, 2012. amount of an inhibitor of the Hippo-YAP signaling pathway. Patent Application Publication Jun. 11, 2015 Sheet 1 of 43 US 2015/O157584A1 A B is 0x. 8 (AD six Patent Application Publication Jun. 11, 2015 Sheet 2 of 43 US 2015/O157584A1 GT Patent Application Publication Jun. 11, 2015 Sheet 3 of 43 US 2015/O157584A1 ?**** H-HZ(61-I s: :: S: Patent Application Publication Jun. 11, 2015 Sheet 4 of 43 US 2015/O157584A1 . i 3888-: Fig. 3 Patent Application Publication Jun. 11, 2015 Sheet 5 of 43 US 2015/O157584A1 8A S18 8: wir s' - c. 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Fig. 22A-B Patent Application Publication Jun. 11, 2015 Sheet 29 of 43 US 2015/O157584A1 Fig. 22C-D Patent Application Publication Jun. 11, 2015 Sheet 30 of 43 US 2015/O157584A1 Fig. 22E-G Patent Application Publication Jun. 11, 2015 Sheet 31 of 43 US 2015/O157584A1 : Patent Application Publication Jun. 11, 2015 Sheet 32 of 43 US 2015/O157584A1 Fig. 24 Patent Application Publication Jun. 11, 2015 Sheet 33 of 43 US 2015/O157584A1 87-V/GZ ‘61-I 6e-soud Patent Application Publication Jun. 11, 2015 Sheet 34 of 43 US 2015/O157584A1 sep XS eudoet & x : eer in a x 8: 8x: x : toe oidso Patent Application Publication Jun. 11, 2015 Sheet 35 of 43 US 2015/O157584A1 s Patent Application Publication Jun. 11, 2015 Sheet 36 of 43 US 2015/O157584A1 88-888 8-883. 838:38 F - + 8: p888-88 :8:8883 *:::::::: Fig. 26A-F Patent Application Publication Jun. 11, 2015 Sheet 37 of 43 US 2015/O157584 A1 s www.: is ex-tag (xxxi & six .ats: 3 sistix. as is 8. ... : : ::::: :::::::: *:::: Fig. 27A-E Patent Application Publication Jun. 11, 2015 Sheet 38 of 43 US 2015/O157584A1 -- Six phi C.2s. 8 3X. ph O2 888 Flag-YAP 08-tag iii. iycito YAx his phos-tag poRE8 G---. E8 0 2 5 O 2 5 K's 20 in Flag-YAP Ex3-tag AX Fig. 28A-C Patent Application Publication Jun. 11, 2015 Sheet 39 of 43 US 2015/O157584A1 Fig. 29A-C Patent Application Publication Jun. 11, 2015 Sheet 40 of 43 US 2015/O157584A1 &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&#3 Fig. 29D-F Patent Application Publication Jun. 11, 2015 Sheet 41 of 43 US 2015/O157584A1 six y Kii anneley Patent Application Publication Jun. 11, 2015 Sheet 42 of 43 US 2015/O157584A1 A. 8. s x 88: Fig. 30A-G Patent Application Publication Jun. 11, 2015 Sheet 43 of 43 US 2015/O157584A1 s Apoptosis Proliferation Fig. 31 US 2015/O157584 A1 Jun. 11, 2015 INHIBITORS OF HIPPO-YAP SIGNALING that promote proliferation and inhibit apoptosis (Zhao et al., PATHWAY Genes Dev (2008) 22:1962-1971). Phosphorylation of YAP by Lats 1/2 kinases can also promote its ubiquitination-depen CROSS-REFERENCE TO RELATED dent degradation (Zhao et al., Genes Dev (2010) 24:72-85). APPLICATIONS TAZ is a YAP paralog in mammals and is also regulated by the 0001. This application is a U.S. national phase filing under Hippo-YAP pathway through both cytoplasmic retention and 35 U.S.C. S371 of Intl. Appl. No. PCT/US2013/043752, filed proteasome degradation (Lei et al., Mol Cell Biol (2008) on May 31, 2013, which claims the benefit under 35 U.S.C. 28:2426-2436). S119(e) of U.S. Provisional Application No. 61/658,084, 0006. In transgenic mice, Yap promotes liver enlargement filed on Jun. 11, 2012, and U.S. Provisional Application No. in a reversible manner (Camargo et al., Curr Biol (2007) 61/658,796, filed on Jun. 12, 2012, which are hereby incor 17:2054-2060; Dong et al., Cell (2007) 130:1120-1133), sug porated herein in their entireties for all purposes. gesting organ size control relies on tight regulation of Hippo YAP pathway activity. Sustained YAP expression results in STATEMENT OF GOVERNMENTAL SUPPORT hyperplasia or tumor development (Dong et al., 2007, Supra), and genetic ablation of Hippo-YAP pathway components in 0002 This invention was made with government support mice also leads to tumor formation (Benhamouche et al., under Grant No. 5R01 CA132809, awarded by the National Genes Dev (2010) 24:1718-1730; Cai et al., Genes Dev Institutes of Health. The government has certain rights in the (2010) 24, 2383-2388; Lee et al., Proc Natl Acad Sci USA invention. (2010) 107:8248-8253: Lu et al., Proc Natl Acad Sci USA (2010) 107:1437-1442; Xu et al., Cancer (2009) 115:4576 FIELD OF THE INVENTION 4585; Zhang et al., Dev Cell (2010) 19:27-38; Zhou et al., 0003. The present invention relates to preventing, reduc Cancer Cell (2009) 16:425-438). Moreover, abnormal acti ing, delaying or inhibiting the proliferation, growth, migra vation of YAP and TAZ has been associated with human tion and/or metastasis of cancer by administering an effective cancers (Overholtzer et al., Proc Natl AcadSci USA (2006) amount of an inhibitor of the HIPPO-YAP signaling pathway.
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