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(12) United States Patent (10) Patent No.: US 6,890,933 B1 Feng Et Al

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(12) United States Patent (10) Patent No.: US 6,890,933 B1 Feng Et Al USOO6890933B1 (12) United States Patent (10) Patent No.: US 6,890,933 B1 Feng et al. (45) Date of Patent: May 10, 2005 (54) KINESIN INHIBITORS Hagan, et al., “Kinesin-related cut7 protein associates with mitotic and meiotic spindles in fission yeast Nature, 356: (75) Inventors: Yan Feng, Brookline, MA (US); Tarun 74-76, 1992. M. Kapoor, New York, NY (US); Hamel, E., “Antimitotic Natural Products and Their Inter Thomas Mayer, Brookline, MA (US); actions with Tubulin', Med. Res. Rev. 16: 207-231, 1996. Zoltan Maliga, East Brunswick, NJ He, et al., “A Simplified System for Generating Recombi (US); Timothy J. Mitchison, nant Adenoviruses', Proc. Natl. Acad. Sci. USA., 95: Brookline, MA (US); Justin Yarrow, 2509-2514, 1998. Boston, MA (US) Hirokawa, “Kinesin and Dynenin Superfamily Proteins and (73) Assignee: President and Fellows of Harvard the Mechanisms of Organelle Transport Science, 279: College, Cambridge, MA (US) 519–526, 1998. Hirschberg, et al., “Kinetic Analysis of Secretory Protein (*) Notice: Subject to any disclaimer, the term of this Traffic and Characterization of Golgi to Plasma Membrane patent is extended or adjusted under 35 Transport Intermediates in Living Cells' J. Cell Biol. 143: U.S.C. 154(b) by 0 days. 1485–1503, 1998. Hoyt, et al., “Two Saccharomyces cerevisiae kinesin-related (21) Appl. No.: 09/791,339 gene products required for mitotic Spindle assambly J. Cell Biol. 118: 109-120, 1992. (22) Filed: Feb. 23, 2001 Hung, et al., “Understanding and Controlling the Cell Cycle Related U.S. Application Data with Natural Products” Chem. Biol. 3: 623–639, 1996. (60) Provisional application No. 60/184,540, filed on Feb. 24, Hyman, et al., “Microtubule-motor activity of a yeast con 2000. tromere-binding protein complex” Nature, 359: 533-536, 1992. (51) Int. Cl." ..................... A61K 31/437; CO2D 471/04 Kapoor, et al., “Allele-Specific Activators and Inhibitors for (52) U.S. Cl. ............................ 514/292; 546/85; 546/86 Kinesin' Proc. Natl. Acad. Sci., U.S.A., 96: 9106–9111, (58) Field of Search ............................ 514/292; 546/85, 1999. 546/86 Kung, et al., “Preparation of Chiral, C-Protected C-Amino Aldehydes of High Optical Purity and Their Use as Con (56) References Cited densation Components in a Linear Synthesis Strategy”, J. U.S. PATENT DOCUMENTS Am. Chem. Soc. 121: 8401-8402, 1999. Leonard, et al., “A One-Pot Tandem Pictet-Spengler-Diels 6,030,983 A * 2/2000 Behforouz et al. ......... 514/292 Alder Synthesis of Apoyohimbines From 3-Carbometh FOREIGN PATENT DOCUMENTS oxy-2 (Formylmethyl)-3-Sulfolene” Tet. Lett. 38: 3071-3074, 1997. WO WO OO/07017 2/2000 Lockhart, et al., “Kinetic Evidence for Low Chemical Pro OTHER PUBLICATIONS cessivity in ncd Eg5” J. Mol. Biol. 273: 160-170, 1997. Ishida, J. et al. : Antitumor agents 201. Cytotoxicity of Mayer, et al., “Small Molecular Inhibitor of Mitotic Spindle Harmine and beta-Carboline analogs. Bioorg. & Med. Bipolarity Identified in a Phenotype-Based Screen” Science, Chem. Lett. vol. 9, pp. 3319-3324, 1999.* 286: 971-974, 1999. Berge, et al., “Pharmaceutical Salts' J. Pharmaceutical (Continued) Sciences, 66:1-19, 1977. Blangy, et al., “Phosphorylation by p34.cdc2 Regulates Primary Examiner-Charanjit S. Aulakh Spindle Association of Human Eg5, a Kinesin-Related (74) Attorney, Agent, or Firm-Brenda Herschbach Jarrell; Motor Essential for Bipolar Spindle Formation in Vivo” Nadege M. Lagneau; Choate, Hall & Stewart Cell, 83: 1159, 1995. Bloom, et al., “Cruising along microtuble highways: how (57) ABSTRACT membranes move through the secretory pathway” J. Cell The present invention provides for compounds, Biol. 140: 1277-1280, 1998. compositions, methods and Systems for inhibiting cell Cramer, et al., “Myosin is Involved in Postmitotic Cell growth. More Specifically, the present invention provides for Spreading” J. Cell Biol., 131: 179-189, 1995. methods, compounds and compositions which are capable of Cramer, et al., “Actin-Dependent Motile Forces and Cell inhibiting mitosis in metabolically active cells. Compounds, Motility” Curr. Opin. Cell. Biol. 6: 82-86, 1994. compositions and methods of the present invention inhibit Desai, et al., “Kin I Kinesins are Microtubule-Destabilizing the activity of a protein involved in the assembly and Enzymes” Cell, 96: 69–78, 1999. maintenance of the mitotic spindle. One class of proteins Enos, et al., “Mutation of a Gene that Encodes a Kinesin which acts on the mitotic spindle is the family of mitotic Like Protein Blocks Nuclear Division in A. Nidulans' Cell, kinesins, a Subset of the kinesin Superfamily. 60: 1019-1027, 1990. Gallione, et al., “A Single Amino Acid Substitution in a 19 Claims, 15 Drawing Sheets Hydrophobic Domain Causes Temperature-Sensitive Cell Surface Transport of a Mutant Viral Glycoprotein' J. Virol ogy, 54:374-382, 1985. (1 of 15 Drawing Sheet(s) Filed in Color) US 6,890,933 B1 Page 2 OTHER PUBLICATIONS Ungemach, et al., General Method for the ASSignment of Stereochemistry of 1,3-Disubstituted 1,2,3, Rousseau, et al., “Synthesis of 3-Deaza-B-Hydroxy 4 Tetrahydro-B-Carbolines by Carbon-13 Spectroscopy J. histidine Derivatives and Their Use for the Preparation of Substituted Pyrrolo2,3-c Pyridine-5-Carboxylates via the Amer: Chem. Soc. 102: 6976–6984, 1980. Pictet-Spengler Reaction”, J. Org. Chem. 63: 2731-2737, Vale, et al., “The Design Plan of Kinesin Motors' Annu. Rev. 1998. Cell Dev. Biol. 13: 745-747, 1997. Sakowicz, et al., “A marine natural product inhibitor of Vale, et al., “Identification of a Nvel Force-Generating kinesin motors' Science, 280: 292-295, 1998. Protein, Kinesin, Involved in Microtubule-Based Motility” Saunders, et al.,"Kinesin-Related Proteins Required for Cell, 42: 39-50, 1985. Structural Integrity of the Mitotic Spindle” Cell, 70: Walczak, et al., “Kinesin-Related Proteins at Mitotic 451–458, 1992. Spindle Poles: Function and Regulation Cell, 85: 943–946, Sawin, et al., “Mitotic Spindle organization by a plus-end 1996. directed microtubule motor' Nature, 359: 540-543, 1992. Sharp, et al., “The Bipolar Kinesin, KLP61F, Cross-Links Walczak, et al., “A Model for the Proposed Roles of Dif Microtubules within Interpolar Microtubule Bundles of ferent Microtubule-Based Motor Proteins in Establishing Drosophila Embryonic Mitotic Spindles”, J. Cell. Biol., 144: Spindle Bipolarity” Curr. Biol., 8:903–913, 1998. 125-138, 1999. Whaley, et al., “The Preparation of 3,4-Dihydroisoquino Steinberg, et al., “Effects of the Myosin Inhibitor 2,3-Bu lines and Related Compounds by the Bischler-Napieralski tanedione Monoxime on the Physiology of Fission Yeast” Reaction” Org. Reaction. 6:74–151, 1951. Eur: J. Cell. Biol. 77: 284-293, 1998. Wood, et al., “CENP-E Is a Plus End-Directed Kinetochore Stockwell, et al., “High-Throuput Screening of Small Mol Motor Required for Metaphase Chromosome Alignment', ecules in Miniaturized Mammalian Cell-Based Assays Cell, 91: 357-366, 1997. Involving Post-Translational Modifications' Chem. Biol. 6(2): 71-83, 1999. * cited by examiner U.S. Patent May 10, 2005 Sheet 1 of 15 US 6,890,933 B1 Compound 22C16 fragments Golgi without affecting interphase microtubule but causes spindle defect VSV-G accumulates in Golgi at 20° C (left). Upon 22C16 treatment, WSW-G accumulates in fragmented Golgi at the same Condition (middle). Golgi is fragmented with 22C16 treatment as shown with GM130 staining (right). 22C16 treatment does not affect interphase microtubule (left, Control; middle, 22Cl6 treated). But monopoie Spindle forms upon 22C16 treatment (right, microtubule in green and chromosomes in blue). FIG. I. U.S. Patent May 10, 2005 Sheet 2 of 15 US 6,890,933 B1 Xenopus Full length Eg5 is also inhibited by the B-carboline in vitro Expected Structure O.8 1. E O. 6 N E 3. 2. 0.4 U O 9 0.2 O.O DMSO B- Wash Control Carboline Out 50 m FIG. 2 U.S. Patent May 10, 2005 Sheet 3 of 15 US 6,890,933 B1 (1) 384-well Assay plate (2) plate stacker (6) automation (3) XY stage xiana routine (4) Z autofocus - image analysis U.S. Patent May 10, 2005 Sheet 4 of 15 US 6,890,933 B1 Golgi Plasma membrane 200 C 320 C FIG. 4 U.S. Patent May 10, 2005 Sheet 5 of 15 US 6,890,933 B1 FIG 5A FIG. 5B F.G. 5C U.S. Patent May 10, 2005 Sheet 6 of 15 US 6,890,933 B1 Golgi ex Golg fragmentat ion FIG. 6 U.S. Patent May 10, 2005 Sheet 7 of 15 US 6,890,933 B1 NADH Enzyme Coupled Assay Lactate --N - NADH Lactate Dehydrogenase -1 ATP Pyruvate S- NAD+ / ADP PEP Kinesin Pyruvate Kinase In the enzyme coupled assay reaction containing LDH, PK PEP, NADH, and ATP, one can measure the rate of ATP hydrolysis because under these reaction Conditions, there is an instantaneous conversion of ADP to ATP resulting in a stoichiometric oxidation of NADH to NAD+ that can be measured as a decrease in NADH fluorescence. FIG. 7A U.S. Patent May 10, 2005 Sheet 8 of 15 US 6,890,933 B1 NADH Enzyme Coupled Assay Typical ATPase Measurement an nO ATP S. C) O C CD 9 10 OUM g ATP g 1mM Z ATP O 200 400 6OO 800 time (s) Advantages: 1. Steady ATP concentration. 2. No buildup of ATP hydrolysis products that may result in feedback inhibition. 3. Many timepoints from a single reaction. FIG. 7B U.S. Patent May 10, 2005 Sheet 12 0f 15 US 6,890,933 B1 HO Q-- U.S. Patent May 10, 2005 Sheet 13 Of 15 US 6,890,933 B1 ?uOD?u??oque0-9JoSuo??eD?J?pouupuesæA?e^?uÐpgos?s??quÁS U.S. Patent May 10, 2005 Sheet 14 of 15 US 6,890,933 B1 (}) N O o*N }} ÇO U.S.
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