USO09552457B2 (12) United States Patent (10) Patent No.: US 9,552.457 B2 Jones et al. (45) Date of Patent: Jan. 24, 2017 (54) REPROGRAMMING EFFECTOR PROTEIN A61 K3I/4709 (2013.01); A61 K3I/5375 INTERACTIONS TO CORRECT (2013.01); C40B 30/02 (2013.01); G06F EPGENETIC DEFECTS IN CANCER 19/706 (2013.01) (58) Field of Classification Search (71) Applicant: BRITISH COLUMBIA CANCER None AGENCY BRANCH, Vancouver (CA) See application file for complete search history. (72) Inventors: Steven J. M. Jones, Vancouver (CA); Oleksandr Yakovenko, Vancouver (56) References Cited (CA); Silvia Thoene, Vancouver (CA); Pierre Yulmin Cheung, Vancouver U.S. PATENT DOCUMENTS (CA); Jianghong An, Vancouver (CA) 3,257.274 A 6/1966 Loprieno et al. 3,466,274 A 9, 1969 De Ridder (73) Assignee: BRITISH COLUMBIA CANCER 3,622,580 A 11/1971 Hromatka et al. AGENCY BRANCH, Vancouver (CA) 2009/O137508 A1 5/2009 McSwiggen et al. 2011/0237606 A1 9, 2011 Chai et al. (*) Notice: Subject to any disclaimer, the term of this 2011 O251216 A1 10/2011 Chinnaiyan et al. patent is extended or adjusted under 35 2012,007 1418 A1 3/2012 Copeland et al. U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 14/381,588 CA WO 2013059944 5, 2013 EP O156785 A1 10, 1985 (22) PCT Filed: Feb. 27, 2013 EP WO2012O123119 A1 9, 2012 GB WO 2010.064019 6, 2010 (86). PCT No.: PCT/CA2O13/OSO145 WO 2007136790 A2 11/2007 WO WO2O09015283 A2 1, 2009 S 371 (c)(1), WO WO 2010O45199 4/2010 (2) Date: Aug. 27, 2014 WO WO 2010094009 8, 2010 WO WO 2011014825 2, 2011 WO WO2O110 143669 A2 11/2011 (87) PCT Pub. No.: WO2013/127011 WO WO2012O71469 A2 5, 2012 PCT Pub. Date: Sep. 6, 2013 WO WO2012O116170 A1 8, 2012 (65) Prior Publication Data OTHER PUBLICATIONS US 2015/O1543.45 A1 Jun. 4, 2015 Mund et al. Bioassays, 32: 949-957, 2010.* New Zealand Intellectual Property Office, Office Action issued in Related U.S. Application Data New Zealand Patent Application No. 700058, Aug. 17, 2015, 4 pageS. (60) Provisional application No. 61/637.282, filed on Apr. European Patent Office, Search Report issued in European Patent 24, 2012, provisional application No. 61/603,650, Application No. 13754077.9. Sep. 25, 2015, 6 pages. filed on Feb. 27, 2012. Santiago, C., et al., “Druggability of Methyl-Lysine Binding Sites.” Journal of Computer-Aided Molecular Design, vol. 25, No. 12, Dec. (51) Int. Cl. 7, 2011, pp. 1171-1178. G06F 9/16 (2011.01) (Continued) A6 IK3I/37 (2006.01) A6 IK 3/47 (2006.01) A6 IK 3/46 (2006.01) Primary Examiner — Michael Borin A6 IK3I/It (2006.01) (74) Attorney, Agent, or Firm — Laura M. Lloyd: Leech A6 IK3I/35 (2006.01) Tishman Fuscaldo & Lampl A6 IK3I/I67 (2006.01) A6 IK 3L/245 (2006.01) A6 IK3I/36 (2006.01) (57) ABSTRACT A6 IK 3/407 (2006.01) Methods of “reprogramming epigenetic mark readers or A 6LX 3/5.375 (2006.01) erasers to recognize epigenetic marks other than their cog C4OB 30/02 (2006.01) nate (or natural) marks are provided. Reprogramming the G06F 9/00 (2011.01) reader or eraser can offset the effects of aberrant writer A6 IK3I/343 (2006.01) activity (for example, loss of function or overactivity) that A 6LX 3L/24709 (2006.01) can contribute to certain diseases states, such as cancer. The (52) U.S. Cl. use of the reprogramming compounds identified by these CPC ............... G06F 19/16 (2013.01); A61 K3I/10 methods in the treatment of Such disease states is also (2013.01); A61K 31/135 (2013.01); A61 K provided. Exemplary mark readers that can be targeted by 3 1/137 (2013.01); A61K 3 1/167 (2013.01); these methods include BPTF and CBX2. A6 IK3I/245 (2013.01); A61K 3 1/343 (2013.01); A61 K3I/36 (2013.01); A61 K 31/407 (2013.01); A61 K3I/47 (2013.01); 13 Claims, 14 Drawing Sheets US 9,552.457 B2 Page 2 (56) References Cited Morin, et al., “Somatic mutation of EZH2 (Y641) in Follicular and Diffuse Large B-cell Lymphomas of Germinal Center Origin.” 2010, Nat. Genet., 42(2): 181-185, NIH. OTHER PUBLICATIONS Musselman, C. A. et al., “PHD fingers: epigenetic effectors and Lutz, Robert E., et al., “Antimalarials C-Alkyl and potential drug targets'. Mol. Interv. Dec. 2009, 9 (6), 314-323. Dialkylaminomethyl-2-phenyl-4-quinolinemethanols”, Journal of Ng, S. S. et al., “Dynamic protein methylation in chromatin biol the American Chemical Society, vol. 68, No. 9, Sep. 1, 1946, pp. ogy”. Cell. Mol. Life Sci., Feb. 2009, 66 (3), 407-422. 1813-1831. Nose, S. et al., "Constant pressure molecular dynamics for molecu Berendsen, H. et al., “Interaction Models for Water in Relation to lar systems.” Mol. Phys. 1983, 50:1055-1076. Protein Hydration.” B. Pullman (ed.), Intermolecular Forces, 1981 Nose, S., “A molecular dynamics method for simulations in the pp. 331-342, D. Reidel Publishing Company. canonical ensemble.” Mol. Phys. 2002, 100:191-198, Taylor & Berendsen, H. J. C. et al., “Molecular dynamics with coupling to Francis Ltd. an external bath,” J. Chem. Phys. 181 (8), Oct. 15, 1984, pp. Parrinello, M. et al., “Polymorphic transitions in single crystals: A 3684-3690, American Institute of Physics. new molecular dynamics method.” J. Appl. Phys. 1981, 52:7182 Campagna-Slater, V. et al., “Pharmacophore Screening of the Pro T190. tein Data Bank for Specific Binding Aite Chemistry”. J. Chem. Inf. Pasqualucci, L. et al., “Analysis of the coding genome of diffuse Model. Mar. 2010, 50 (3), pp. 358-367, American Chemical Soci large B-cell lymphoma,” Nat. Genet. Jul. 31, 2011; 43(9):830-837. ety. Nature America, Inc. Cerny, V., “Thermodynamic Approach to the Traveling Salesman Pati, H.N. et al., "o-Substituted I-Aryl-3-dimethylaminopropanone Problem: An Efficient Simulation Algorithm.” JOTA vol. 45, No. 1, Hydrochlorides: Potent Cytotoxins towards Human WilDr Colon Jan. 1985, pp. 41-51. Plenum Publishing Corporation. Cancer Cells', Chemical & Pharmaceutical Bulletin, 2007, 55(4), Dimmock, J. R., et al., “Cytotoxic and anticancer activities of 511-515, Pharmaceutical Society of Japan. Somel-aryl-2-dimethylaminomethyl-2-propen-I-one hydrochlo Quinn, A. M. et al., “Methods for Activity Analysis of the Proteins rides”, Pharmazie, 1998, 53(10), 702-706. that Regulate Histone Methylation'. Current Chemical Genomics. Essmann, U. et al., “A Smooth particle mesh Ewald method.” J. 2011, 5 (Suppl. I-M6), 95-105, Bentham Open. Chem. Phys. 1995, 103.8577-8593. Rotili. D. and Mai, A., “Targeting Histone Demthylases: A Newe Grauffel, C. et al., “Force field parameters for the simulation of Avenue for the Fight Against Cancer.” 2011, Genes & Cancer, modified histone tails”. J. Comput. Chem. Oct. 2010, 31 (13), pp. 2:663-679. 2434-2451, Wiley Periodicals, Inc. Ruthenburg et al., “Recognition of a mononucleosomal histone Gui, et al., “Frequent mutations of chromatin remodeling genes in modification pattern by BPTF via multivalent interactions.” 2011, transitional cell carcinoma of the bladder,’ 2011, Nat. Genet. Cell, 145(5):692-706, Elsevier, Inc. 43:875-878. Schuttelkopf, A. W. et al., “PRODRG: a tool for high-throughput Herold, J. M. et al., “Drug discovery toward antagonists of methyl crystallography of protein-ligand complexes.” Acta Cryst. D Biol. lysine binding proteins”. Current Chem. Genomics, Aug. 2011, 5 Crystallography 2004, 60:1355-1363, International Union of Crys (Suppl-M2), pp. 51-61, Bentham Open. tallography. Hoover, W. “Canonical dynamics: Equilibrium phase-space distri Scott, W. et al., “The GROMOS Biomolecular Simulation Program butions.” Physical Review. A 1985, 31: 1695-1697. The American Package.” J. Phys. Chem. A 1999, 103, 3596-3607, American Physical Society. Chemical Society. Humphrey, W.; et al., “VMD: Visual Molecular Dynamics,” J. Mol. Sneeringer, et al., "Coordinated activities of wild-type plus mutant Graph. 1996, 14:33-8, 27-8. Elsevier Science Inc. EZH2 drive tumor-associated hypertrimethylation of lysine 27 on Kaustov, L. et al., “Recognition and specificity determinants of the histone H3 (H3K27) in human B-cell lymphomas,” 2010, Proc. human CbX chromodomains”, Journal of Biological Chemistry, Jan. Natl. Acad. Sci. U. S. A., 107:20980-20985, Epizyme, Inc. 7, 2011, 286 (1), 521-529. Watanabe, et al., “Frequent Alteration of MLL3 Frameshift Muta Kirkpatrick, S. et al., "Optimization by Simulated Annealing.” tions in Microsatellite Deficient Colorectal Cancer,’ PLoS One, Science 1983, 220:671-680. Aug. 2011, vol. 6, Issue 8, e23320, pp. 1-8. Kunkel, M.W. et al., “Cell line-directed screening assay for inhibi Yap, et al., “Somatic mutations at EZH2 Y641 act dominantly tors of thioredoxin reductase signaling as potential anti-cancer through a mechanism of selectively altered PRC2 catalytic activity, drugs' Anti-Cancer Drug Design, 1997. 12(8), 659-670, Oxford to increase H3K27 trimethylation.” Blood, Feb. 24, 2011, vol. 117. University Press. No. 8, pp. 2451-2459. The American Society of Hematology. Lemkul. J. A. et al., “Practical Considerations for Building Ziemin-Van Der Poel, et al., “Identification of a gene, MML, that GROMOS-Compatible Small Molecule Topologies,” J. Chem. Inf. spans the breakpoint in 11q23 translocations associated with human Model. 2010, 50:2221-2235, American Chem. Society. leukemias.” Proc. Natl. Acad. Sci. USA vol. 88, pp. 10735-10739, Li H., et al., “Structural Basis for Lower Lysine Methylation Dec. 1991 Medical Sciences. State-Specific Readout by MBT Repeats of L3MBTL1 and an British Columbia Cancer Agency Branch, International Search Engineered PHD Finger.” 2007, Mol. Cell., 28:677-691, Elsevier Report and Written Opinion of the International Searching Author Inc. ity, International Patent Application No. PCT/CA2013/050145, Li, H., et al., “Molecular basis for site-specific read-out of histone Canadian Intellectual Property Office, May 27, 2013.