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(12) Patent Application Publication (10) Pub. No.: US 2009/0076019 A1 Tyers Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0076019 A1 Tyers Et Al US 20090076019A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0076019 A1 Tyers et al. (43) Pub. Date: Mar. 19, 2009 (54) METHODS FOR TREATING Publication Classification NEUROLOGICAL DISORDERS OR DAMAGE (51) Int. Cl. Inventors: Mike Tyers, Toronto (CA); Phedias A63/496 (2006.01) (75) CI2O 1/02 (2006.01) Diamandis, Toronto (CA); Peter B. A6II 3/445 (2006.01) Dirks, Toronto (CA) A63/64 (2006.01) Correspondence Address: A6IP 25/00 (2006.01) HOWSON AND HOWSON A6IP 25/6 (2006.01) SUITE 210,501 OFFICE CENTER DRIVE A6IP 25/18 (2006.01) FT WASHINGTON, PA 19034 (US) (52) U.S. Cl. ...................... 514/252.13:435/29: 514/317; 514f613 (73) Assignees: Mount Sinai Hospital, Toronto (CA); HSC Research and Development Limited (57) ABSTRACT Partnership, Toronto (CA) A clonogenic neurosphere assay is described that carries out high throughput screens (HTS) to identify potent and/or (21) Appl. No.: 11/871,562 selective modulators of proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/ (22) Filed: Oct. 12, 2007 or self-renewing and multipotent neural stem cells (NSCs). Compositions comprising the identified modulators and Related U.S. Application Data methods of using the modulators and compositions, in par (60) Provisional application No. 60/851,615, filed on Oct. ticular to treat neurological disorders (e.g. brain or CNS can 13, 2006. cer) or damage are also disclosed. Neurosphere Stein Progenitor Differentiated eEE eEE t Prolifefatic Assay Patent Application Publication Mar. 19, 2009 Sheet 1 of 26 US 2009/0076019 A1 Figure 1 Neurosphere Progenitor O Defeitiated e CE M. Proliferation Assay Patent Application Publication Mar. 19, 2009 Sheet 2 of 26 US 2009/0076019 A1 Figure 2 a 1.5 ES 1.0'' O G) N is 0.5 Z 0.0 Compound Number Patent Application Publication Mar. 19, 2009 Sheet 3 of 26 US 2009/0076O19 A1 Figure 2 b (0.03% DMso) 3 M cyc Naloxone Patent Application Publication Mar. 19, 2009 Sheet 4 of 26 US 2009/0076O19 A1 Figure 3a Patent Application Publication Mar. 19, 2009 Sheet 5 of 26 US 2009/0076O19 A1 Figure 3b Patent Application Publication Mar. 19, 2009 Sheet 6 of 26 US 2009/0076O19 A1 Figure 3c Patent Application Publication Mar. 19, 2009 Sheet 7 of 26 US 2009/0076O19 A1 Figure 3d Patent Application Publication Mar. 19, 2009 Sheet 8 of 26 US 2009/0076O19 A1 Figure 3e Patent Application Publication Mar. 19, 2009 Sheet 9 of 26 US 2009/0076O19 A1 Figure 3f Patent Application Publication Mar. 19, 2009 Sheet 10 of 26 US 2009/0076019 A1 Figure 3g k 80 2000 Cells Well 10 00 Cells Well H- -- anºN.franaisauðudso &=º??s?g?eºg |ddwyd =—••a | ?upordu=#| aut?duourodº| eoeuequadºqº?qu DSO Ethno H2O Patent Application Publication Mar. 19, 2009 Sheet 11 of 26 US 2009/0076O19 A1 Figure 4 3. b E d O 10° 10' 10° 10° 10' CD133-PE 3. o d E E 92 2.083 as t 2.5" 5 f S s 8 - 2 S.s > 9 as S T ar SS E 1.126 g . 1.5 5. s i O O l 5 3. L N as S ch n O 1 5 O46O7 C s n C 0.168 O. 1865 6 O.1682 ?h 0.5 -l O.02O6 Dopamine Dopamine Acetylcholine NMDA Opioid Serotonin Vanilloid Agonist Antagonist Antagonist Antagonist Agonist Agonist Agonist sh Doppine Serotonin x: Muscarinic s A. i oals th N NSC otch/ Varioid DMSO Ethanol HO Proliferation, Self-Renewal, Differentiation, Survival Patent Application Publication Mar. 19, 2009 Sheet 12 of 26 US 2009/0076019 A1 Figure 5 2 le { } { ison 1 | * * d d this } w s 4. te 0.8 o (a 0.6 Negativeegative UontroControl is Positive Control O 0.4 Z-Factor = 0,78 " N 0.2 (t ) s S S S S S S & S S S S S S S S S S S S & S S S S & S S & Z O 5. 5 2 25 3) b Sample Number 0.8 0.6 0.4 O O2 0.4 06 0.8 2 4 6 Replicate 2 (Normalized) Patent Application Publication Mar. 19, 2009 Sheet 13 of 26 US 2009/0076019 A1 WO513 V 8879 V 1377 T 6318 S O09 S 7067 i...o.o.o. s: S 4692 ASRSREASE R 104 -------------- 3. O 3251 P 8511 P 6402 P 0547 N 7778 N 7758 M 149 M 120 H M 105 rt M 001 M3668 M 2537 M 1022 151 i 2892 H 127 H 7779 F 114 E 1383 i. D 027 as D 8008 o D. 7815 D 3768 D 2926 C 106 C 7698 if C 4662 C 2932 C 2538 ionow, B 168 B5016 - E B 5002 A 140 A 4393 DMSO N wn O w N O O O Normalized Cell Counts (MTT) Patent Application Publication Mar. 19, 2009 Sheet 14 of 26 US 2009/0076O19 A1 Figure 7 Patent Application Publication Mar. 19, 2009 Sheet 15 of 26 US 2009/0076O19 A1 Normalized MTT C d --- - H s | N as asE z . Plate Number "1 2 3 4 5 67 8 g 1011121314 1516 Plate Number Patent Application Publication Mar. 19, 2009 Sheet 16 of 26 US 2009/0076019 A1 Figure 9 in Braurors stee other Turnors Before diagonsis First year of follow-up 1-9 years of follow-up 10+ years of follow-up Patent Application Publication Mar. 19, 2009 Sheet 17 of 26 US 2009/0076O19 A1 Figure 10 s os- o 2 02: 02: 00- 0.0 set a - - WW -2 to - - - -: -lo - - - - Cycloheximide) (M) Etoposide (M) Carboplatin) (M) to as0.8; a 5 -X-X a as Dihydrocapsaicin (M) E(R)-Apomorphine) (M) g 8 O 70; Eccles pers s it is 60 3. g : s: s: 5 O P=0.08 P-0.03 P=0.01 P=10 P-10 P.108 24.3 O:OO &l - - - - - (PAPP (M) 0 - - Patent Application Publication Mar. 19, 2009 Sheet 18 of 26 US 2009/0076O19 A1 Figure 11 -- Weice (ethario b 2-1 tire 8 rear 1 --are toposite rosew ty r is , sk - so ferri .. 3 : 6 isSt. 4 : w 2 is ce. , s e White is prod PAFP topside Tirne (hy C 3.5 - trait d fic 3. 43 at it is far prodi as isotype s , "a ... 2. ----- . s "Fat . 8É s WOOD "f s ", && ------ Vehicle if engrad PAPP Etoposide to t Patent Application Publication Mar. 19, 2009 Sheet 19 of 26 US 2009/0076O19 A1 Figure 12 a to e squindo s 3 33 - - M-supiric --- 0.95 Mitsu price m mi. S.O. Bronocriptine (M) Patent Application Publication Mar. 19, 2009 Sheet 20 of 26 US 2009/0076O19 A1 Figure 12 f Bromocriptine Bromocriptine + sulpiride (1.25 piM) (0.3 uM) Bromocriptine + sulpiride (0.95 uM) (3 uM) Untreated (9.5 p.M) Patent Application Publication Mar. 19, 2009 Sheet 21 of 26 US 2009/0076O19 A1 Figure 13 a C H N N ^^-OH AN2. HO C" N C e N/- N C 6 HO C. C. S N f N \ CrC C 6 26 43 44 Apomorphine Perphenazine L-745,870 4-Chloro-3-alpha Cluster 84 Cluster 130 Cluster 44 (diphenylmethoxy)tropane p-value = 8.86E-30 p-value = 9.03E-29 p-value = 8.86E-30 Cluster 129 Target(s): DRD1a Target(s): DRD1a, Target(s): DRD4 p-value = 1.98E-22 DRD2, DRD4 DRD2, ADRA1a Target(s): Reuptake Blocker H S OH O H/, N 1/ H n-1N “c N-1- N "y O N 45 46 Pergolide (E)-7-Hydroxy-DPAT 47 4. Cluster 51 Cluster 8 S-(-)-Eticlopride (+)-Butaclamol p-value = 3.95E-03 p-value = 6.12E-29 Cluster 126 Custer 68 Target(s): DRD1, Target(s): DRD2, p-value = 1.25E-07 p-value = 8.86E-30 DRD2, 5-HT2B DRD3 Target(s): DRD2, Target(s): DRD11 DRD3 DRD21, NaCh, 5-HT1F Patent Application Publication Mar. 19, 2009 Sheet 22 of 26 US 2009/0076O19 A1 Figure 13 b NH NH VN ls.l. N l O ( ) N. NH2 e F C H s N F F O F 48 49 50 R(+)-UH-301 3-Tropanyl-3,5- -Phenylbi 40 s 12. dichlorobenozater Cluster ybiguanide136 SS:angleton t . 92E-03 Custer 29 p-value = 3.58E-03 p-value = 5.01 E-03 arge (s): 5-HT1A p-value = 9.09E-10 Target(s): 5-HT3 Target(s): s HT1B Target(s): 5-HT3 get(s): 5 NN N O ClN1 N N 2-N N O O N O N ( ) O O ( N) (N ) C O F N ( ) F H2N O F C /Non 14 51 52 53 PAPP Trazodone SB 224289 SE: 2O4O7O Cluster 94 (singleton) Custer 122 Cluster 11 Cluster 116 (singleton) p-value = 3.78E-27 p-value F 4,10E-03 p-value = 8.52E-07 p-value = 1.98E-09 Target(s): 5-HT1A, Target(s): 5-HT2A, Target(s): 5-HT1B Target(s): 5-HT4 Patent Application Publication Mar. 19, 2009 Sheet 23 of 26 US 2009/0076019 A1 Figure 14 a 3. inactive active Patent Application Publication Mar. 19, 2009 Sheet 24 of 26 US 2009/0076019 A1 Figure 14 b inactive Patent Application Publication Mar. 19, 2009 Sheet 25 of 26 US 2009/0076O19 A1 Figure 15 a. 26 68 70 iv. inactive 69 N F N F COrrS 72 vi. 71 Wii. Patent Application Publication Mar. 19, 2009 Sheet 26 of 26 US 2009/0076O19 A1 Figure 15 b iii.
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