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(12) Patent Application Publication (10) Pub. No.: US 2014/0051633 A1 Harding Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0051633 A1 Harding Et Al US 20140051633A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0051633 A1 Harding et al. (43) Pub. Date: Feb. 20, 2014 (54) HEPATOCYTE GROWTH FACTOR MIMICS (60) Provisional application No. 61/706,567, filed on Sep. AS THERAPEUTICAGENTS 27, 2012, provisional application No. 61/706,437, filed on Sep. 27, 2012. (71) Applicant: Washington State University, Pullman, WA (US) Publication Classification (72) Inventors: Joseph W. Harding, Pullman, WA (US); John W. Wright, Pullman, WA (US); (51) Int. C. Caroline C. Benoist, Nashville, TN C07K5/065 (2006.01) (US); Leen H. Kawas, Pullman, WA (52) U.S. C. (US); Gary A. Wayman, Pullman, WA CPC .................................. C07K5/06078 (2013.01) (US) USPC ........................................................... S14/95 (73) Assignee: Washington State University, Pullman, WA (US) (57) ABSTRACT (21) Appl. No.: 14/038,973 (22) Filed: Sep. 27, 2013 Small molecule, peptidic hepatocyte growth factors mimics, which act as both mimetics and antagonists, have been gen Related U.S. Application Data erated. These molecules have been shown or predicted to have (63) Continuation-in-part of application No. PCT/US2012/ therapeutic potential for numerous pathologies including 031815, filed on Apr. 2, 2012. dementia (e.g. Alzheimer's) and Parkinson's disease. Patent Application Publication Feb. 20, 2014 Sheet 1 of 40 US 2014/0051633 A1 a --- --- - - -s ------- CS -8- Scopolarine s -k- Oii exa-ow " -: N. Sks s i. Y s re. Dihexa-high as: ^ N.-- st-scs:- -------------------------------------------------------------------------------------------. Acquisition (days) Figure 1A -8-CSF -- -8- Scopoanine i. --- - -k- Dihexa-ow -- hexa-high reta-or 2 3 4 5 6 7 8 Acquisition (days) Figure 1B -8- vici-treated -- hexa Acquisition (days) Figure 1C Patent Application Publication Feb. 20, 2014 Sheet 2 of 40 US 2014/0051633 A1 Contro Dihexa 10-11M Dihexa 0-3M Dihexa 100M Dihexa iO2M Figure 2A aC 30 & s 8 30 5 st Contro 10"10M Nie-Ang V iO3M Nie-Angiv Figure 2B Patent Application Publication Feb. 20, 2014 Sheet 3 of 40 US 2014/0051633 A1 ------------- g Y CN: ra tiiii OS/Souis O i {{{{3 --e. Patent Application Publication Feb. 20, 2014 Sheet 4 of 40 US 2014/0051633 A1 O.78 wa. OS Control Nie-Ang V Dihexa Figure 4 MRFP-3-Actin WG verged {artifi Nie-Angiv Dihexa &RFP-f-Actin Synapsi verged Citi Nie-Argiv Dihexa MRFP-i-Actin S-35 verged Coto Nie-Argiv Diexa Figure 5A Patent Application Publication Feb. 20, 2014 Sheet 5 of 40 US 2014/0051633 A1 Percent Correlation Number of Spines s se: Control Nie-Ang V Dihexa Control Nie-Argiv 3:hexa Synapsin Synapsin Figure 5B Figure 5C Percert Corelation Number of Spines sa' a-a/ 5 5 s St: Control Nie-Angwi Dhexa VG. iG: Figure 5D Figure 5E Pe:cert Corfeiation: Nutribe? of Spines 50 sks is 40 i; 30 ... &-- 2 40 O Contro Nie-Ang V Dihexa Control 8ie-Argv Dihexa S-35 S-35 Figure 5F Figure 5G Patent Application Publication Feb. 20, 2014 Sheet 6 of 40 US 2014/0051633 A1 w 8 8 4. 2 Contro Nie-Angiv hexa Figure 6A Cottro 10 pA 250 msec Nie-Angiv i8xa Figure 6B Patent Application Publication Feb. 20, 2014 Sheet 7 of 40 US 2014/0051633 A1 Figure 7A S 5 Contro Nie-Argiv Dihexa Figure 7B Patent Application Publication Feb. 20, 2014 Sheet 8 of 40 US 2014/0051633 A1 Corto HGF Sigfrn HGF 20rgin {{GF 2.5mg/mi HGF Origin: Figure 8 Figure 9A Contro Nie-Ang V Dihexa Figure 9B Patent Application Publication Feb. 20, 2014 Sheet 9 of 40 US 2014/0051633 A1 100- 100- S. S. 7s. 75 s & SC C 50 8 25 S. 2S 3. & 3.22. { % Control HGF 1 ng/ml Conto GF rigin: Syriapsi W33 Figure 10A Figure 10B (Cirsi -(- is 100- S. g 3. $ 75 s C. : R. 50 x s sa 2. 25 % s &22222222222 % 23 as {C}rio HGF 10ngmi ar Nier Y Figure 10C Figure 1 OD s f fy s 8 - xxxx s 9f && s & X: a. 4- x & XXX33& XXXXXXXXX 4.a XXX s x. i. { &X8XXX Contro Dihexa Figure 11 Patent Application Publication Feb. 20, 2014 Sheet 10 of 40 US 2014/0051633 A1 es & 3.4. {{ . X 2 r {... g Control 10-3M Dihexa 10-12M Dihexa 2.5ngfrnt HGF Ongimi HGF i Dhexa+ HCFS Figure 12A 3. 2 tri----- - -a-a-a-a-no-mas Coiro HGF2.5ng imi HGF ong? mi Nie-Angiv 10-13 M Nie-Angv 10-12M Niel-Angivi + HGF Figure 12B Patent Application Publication Feb. 20, 2014 Sheet 11 of 40 US 2014/0051633 A1 5. 3 O hinge i + HGFS: 0-8A Hinge 0-328i Hinge iO-2A Hings Ongirn HGF Figure 13A Figure 13B 4- 4. k s 5. 3 y 2 2 . -inge -- { Nie-Ang:Wii''g's into ri5.get irre t(-2, Hiriga 10-12M Nie-Angly 0-2M Hinge G-12. Dihexa Figure 13C Figure 13D Patent Application Publication Feb. 20, 2014 Sheet 12 of 40 US 2014/0051633 A1 „azteinê?: s s ww. {z}- OScitid go Á3:33 8. & c. c. ca ri c. c. (2) CScotti CA38:b8. Patent Application Publication Feb. 20, 2014 Sheet 13 of 40 US 2014/0051633 A1 y SR 8S CER C CCR is - Y - fie: Ai ka Actin 43 kDa 2.38-5 ly SR S 3S "" 2.0e-5. 223. SSRP X8. a COR x: f XX MB X s 1.5et-5 XSSS------ - 3XXX C: 2& Y x s 3 P 8X {i} v X is a1.0e-5 r. x& &XX . XS. & S&& x:XX K : 8 KS& 3.: Figure 15 Patent Application Publication Feb. 20, 2014 Sheet 14 of 40 US 2014/0051633 A1 'se RSx && 8 W s & Control HGF 50ngmi HGF 50rgini+ Dihexa C-12, HGF 400ngmi Dhexa 0-28. Dihexa 0-68. Treatment Groups HGF 50ngfini+ Control HGF 100rgin HGF 50nglin Dhexa 1028 Dhexa 0-12, Dhexa 100M GF 50rg . HGF2.5ng - + i - - - - + - *GF .25ng -- . exa (-13. -- - . Dihexa 0-6 w8 3 Patent Application Publication Feb. 20, 2014 Sheet 15 of 40 US 2014/0051633 A1 Figure 18 shc-Met-6Myc sho-viet-8Myc sho-viet-6Myc Non-transfected C-Met-8Myc (i) (2) (+2} 20.s 3. a 15 3. (i) (.. W K s: 5 Corto 8xa Spines HGF Nei-Angly shielSpines HGF Nie-Anglysitei S Figure 20 Patent Application Publication Feb. 20, 2014 Sheet 16 of 40 US 2014/0051633 A1 ris- a SeaCS -- Scopolarine-a(SF 150- -k- Scoolanine-exa Y M. Scopeianirefigesiliexa at SY sexia hinge-acSF 2 4. 6 8 Acquisition (days) Figure 21 O 8 12. 8O 2a: 3: Time (min) Figure 22 Patent Application Publication Feb. 20, 2014 Sheet 17 of 40 US 2014/0051633 A1 800 a 60000 E 40000 2000. : : { re----------------------as-as-as-a- :: : ... 4 ... 2 - -8 -8 i.ogvi Figure 23 ww.kia) Dina --> 7 38 3S yof Orier- 72 { -- s . -ie-X-i-SAA wet rp CyS Tyr -a- Figure 24A 50 }{- SO HGF Tyr CYS TRP MET compound 10-10M Figure 24B Patent Application Publication Feb. 20, 2014 Sheet 18 of 40 US 2014/0051633 A1 iPiet 140 kDa Treatment groups Figure 26 Patent Application Publication Feb. 20, 2014 Sheet 20 of 40 US 2014/0051633 A1 Carro Trg 0-10a 2}rgini GF Miet 10-8 Figure 27B 1. -8 53" : V My 108 % 5 1 O Patent Application Publication Feb. 20, 2014 Sheet 21 of 40 US 2014/0051633 A1 B6FO + Cys B 16F10 + Cys 100 g/kg/D Qigfkgf Figure 29A SO sa ans 36 Cys Orgfkgiday CyS OOgfkgficiay Figure 29B Patent Application Publication Feb. 20, 2014 Sheet 22 of 40 US 2014/0051633 A1 3. vehicles (a CSF) Scopoiania 8-acety-Niss-Tyr-e-his -Nie-Tyr-is S. GASA-Tyr-e Nie-yr-le-his-aride | training ey Figure 30A 8 2 treatment Groups Figure 3OB Patent Application Publication Feb. 20, 2014 Sheet 23 of 40 US 2014/0051633 A1 glºeun61-I is OS/Sauds joi ..}} OgjSettids Q if Patent Application Publication Feb. 20, 2014 Sheet 24 of 40 US 2014/0051633 A1 tui (SfSeuds go if Patent Application Publication Feb. 20, 2014 Sheet 25 of 40 US 2014/0051633 A1 800 SO 4OOOO 20000 Brain Regions Figure 32 Patent Application Publication Feb. 20, 2014 Sheet 26 of 40 US 2014/0051633 A1 2O 4OOO SCO 88 Time (min) Figure 33 150 g -- Dihexa -8-7-Ethoxyco rain 100 is rais------- -- Weapai f : w -e- ioxican S. 50 . O 2 40 60 8 time (min) Figure 34 Patent Application Publication Feb. 20, 2014 Sheet 27 of 40 US 2014/0051633 A1 s vehicle (aCSP Scopoania Scopeii exai O, no : ScopieXa : {} S fraining Day Figure 35A Vehicle (aSF) Scopotamia Scrip-Eihexa .05mgikg Scop>{ihexa .25rigikg s Scopiihexa 50:ngikg 4. 8 8 Training Day Figure 35B 3 vehicia (aCSF C Scoggiarie Scipatihexa .25ing kg : Scop>ishaxa 2.(ragikg raining Day Figure 35C Patent Application Publication Feb. 20, 2014 Sheet 28 of 40 US 2014/0051633 A1 (38S u2 per u au, Patent Application Publication Feb. 20, 2014 Sheet 29 of 40 US 2014/0051633 A1 8 8. s: 40 C 20 &Y & X. & & N& ve &N3. &S & cS S XS:S S&& * ? g & & t KS & S 3. Š& N S. N& s s s c 2 reatinert Groups Figure 36C 150 a t -8- Vehicle (O) -&- ihexa-2 fingfkg M s 2. s K i. C 3. 4. 6 8 raining Day Figure 37 Patent Application Publication Feb. 20, 2014 Sheet 30 of 40 US 2014/0051633 A1 38€aumôl-ff c 09 re 3 EN --- g99eun614 Lisi OgjS8.
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