US010207988B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 ,207 , 988 B2 Mills et al. ( 45 ) Date of Patent : Feb . 19 , 2019 ( 54 ) METHODS AND COMPOSITIONS FOR 2004 /0015020 AL 1 /2004 Deshpande et al. TREATMENT OF CANCER AND 2004 /0147788 AL 7 /2004 Savouret et al . 2004 /0152629 AL 8 /2004 Hadfield et al. AUTOIMMUNE DISEASE 2009 /0182003 A1 * 7 /2009 Sinclair .. .. .. A61K 31/ 05 514 / 291 (71 ) Applicant: THE JACKSON LABORATORY, Bar 2013 /0184342 AL 7 /2013 Mills et al . Harbor , ME (US ) FOREIGN PATENT DOCUMENTS ( 72 ) Inventors: Kevin David Mills , Bar Harbor, ME (US ) ; Muneer Gulamhusien Hasham , EP 0331983 B1 12 / 1994 WO 2003 /039557 5 / 2003 Ellsworth , ME ( US ) ; Caroline Gardner WO 2003 /039557 AL 5 /2003 McPhee , Seal Cove , ME (US ) WO 2004 /021987 3 / 2004 ( 73 ) Assignee : THE JACKSON LABORATORY, Bar Harbor, ME (US ) OTHER PUBLICATIONS Gundrum et al . ( Investigational New Drugs , 2005 , 23 , 3 - 9 ). * ( * ) Notice : Subject to any disclaimer , the term of this Johnson et al ., ( British J . of Cancer 2001, p . 1424 - 1431 ) . * patent is extended or adjusted under 35 Cecil Textbook of Medicine, 20th Edition , vol . 1 , 1996 . * U . S . C . 154 (b ) by 50 days. Gura et al. (Science 1997 , Nov . 7 , 278 ) . * Silverman (Prodrugs and Drug Delivery Systems, The Organic Chemistry of Drug Design and Drug Action , pp . 352 -401 , 1992 . * ( 21) Appl . No. : 13 /799 ,963 Bundgaard , Design of Prodrugs , 1985 , chapter 1 . * Dorwald , Side Reactions in Organic Synthesis : A Guide to Suc ( 22 ) Filed : Mar. 13, 2013 cessful Synthesis Design 2005 . * Greeve et al . (Blood , 101, 9 , 1 , May 2003 , p . 3574 - 3580 ) * (65 ) Prior Publication Data Jiang et al. ( European J of Pharmacology, 488 , 2004 , 27 -34 ). * Weise et al . (Molecular Cell , 28 , 482 -490 , Nov . 9 , 2007) . * US 2013 /0184342 A1 Jul. 18 , 2013 Klein et al . (DNA repair , 2008 , 686 -693 ) . * ( Cancercompass , https : / /www .cancercompass .com /leukemia Related U . S . Application Data information .htm , 2016 ) . * Lockwood (WWW . Rn .org , Leukemia : AML, CML, ALL and (63 ) Continuation - in -part of application No . PCT/ CLL ) * US2012 /043074 , filed on Jun . 19 , 2012 . Feldhahn ( The J of Experimental Medicine , 2007 , 204 , 5 , 1157 1166 ) . * ( 60 ) Provisional application No . 61/ 501 , 522 , filed on Jun . Wieder et al. ( Leukemia , 2001 , p . 1735 - 1742 ). * Horvat et al. ( Eur J Cancer, vol. 29 A , 132 - 137 , 1993 ). * 27 , 2011 . Badger et al. , Journal of Pharmacology and Experimental Thera peutics , 291( 3 ) :1380 - 1386 ( 1999 ) . " Idoxifene , a novel selective (51 ) Int. CI. estrogen receptor modulator, is effective in a rat model of adjuvant C07C 331 / 30 ( 2006 . 01 ) induced arthritis . " C07C 307 / 10 ( 2006 .01 ) Hasham et al ., Nature Immunology , 11( 9 ): 820 -826 (2010 ) . " Wide C07C 311 /08 ( 2006 .01 ) spread genomic breaks generated by activation - induced cytidine C07C 311 / 14 ( 2006 .01 ) deaminase are prevented by homologous recombination .” GOIN 33 / 50 ( 2006 .01 ) Horvat et al. , European Journal of Cancer, 29 ( 1 ) : 132 - 137 ( 1993 ) . “ Tumour cell proflieration is abolished by inhibitors Na+ H + and A61K 31 / 145 ( 2006 .01 ) HCO3 -CL - exchange . ” C07C 309 /51 ( 2006 .01 ) Hwang et al. , Molecular and Cellular Biochemistry , 327 ( 1 - 2 ) :135 C07C 335 / 20 ( 2006 .01 ) 144 ( 2009 ) . “ Reduction of anion exchanger 2 expression induces (52 ) U .S . CI. apoptosis of human hepatocellular carcinoma cells .” CPC .. 007C 331/ 30 (2013 .01 ) ; A61K 31/ 145 Ishida et al. , Nucleic Acids Research , 37 ( 10 ) : 3367 - 3376 (2009 ) . (2013 .01 ) ; C07C 309 /51 (2013 . 01 ) ; C07C “ DIDS , a chemical compound that inhibits RAD51 -mediated homolo 311/ 08 ( 2013 .01 ) ; C07C 311/ 14 (2013 .01 ) ; gous pairing and strand exchange .” C07C 335 /20 ( 2013 .01 ) ; GOIN 33 /5008 (Continued ) ( 2013 .01 ) ; C07C 2601 /02 ( 2017 .05 ) ; GOIN 2500 / 10 (2013 .01 ) ; GOIN 2800 / 52 (2013 .01 ) Primary Examiner — Umamaheswari Ramachandran (58 ) Field of Classification Search (74 ) Attorney, Agent, or Firm — Nixon Peabody LLP ; None David S . Resnick ; Nicole D . King See application file for complete search history . (57 ) ABSTRACT (56 ) References Cited The technology described herein relates to methods of inducing cell death . The technology described herein further U . S . PATENT DOCUMENTS relates to treating conditions including cancers and autoim 3 , 828 , 060 A 8 / 1974 Lyness et al . mune diseases comprising administering inhibitors of 5 , 569 , 786 A 10 / 1996 Pettit et al. double strand break repair . Also described herein are inhibi 6 ,048 , 903 A 4 / 2000 Toppo et al. tors of double strand break repair and methods of screening 6 , 361, 815 B1 3 / 2002 Zheng et al. for such inhibitors . 6 ,552 ,213 B14 / 2003 Deshpande et al . 6 , 844 , 471 B2 1 / 2005 Despande et al . 7 , 803 , 790 B2 9 / 2010 Chong et al. 1 Claim , 27 Drawing Sheets 2002 / 0058708 Al 5 / 2002 Inman et al. Specification includes a Sequence Listing . US 10 ,207 ,988 B2 Page 2 ( 56 ) References Cited Thomas et al . , “ Manganese triacetate oxidative lactonisation of electron - rich stilbenes possessing catechol and resorcinol substitu tion ( resveratrol analogues ). ” Tetrahedron Lett. 43 :3151 - 3155 ( 2002 ) . OTHER PUBLICATIONS Lao et al . , “ Autophagy Pathway of Raji Cell Death Induced by Resveratrol” , Chinese Journal of Biologicals , 22 ( 7 ) : 654 -658 ( 2009 ) . Kim et al ., International Immunopharmacology, 8 ( 12 ): 1695 - 1702 Li et al ., “ 2 , 34, 4 , 4 , 5 '- Pentamethoxy -trans - stilbene , a resveratrol (2008 ) . “ Piceatannol, a stilbene present in grapes , attenuates dextran derivatve , inhibits colitis - associated colorectal carcinogenesis in sulfate sodium - induced colitis .” Leuenberger et al. , Modern Pathology , 23 ( 2 ) :177 - 186 (2010 ) . “ AID mice” , British Journal of Pharmacology, 160 : 1352 - 1361 (2010 ) . protein expression in chronic lymphocytic leukeia / small lymphocytic Roman et al. , " Analysis of resveratrol - induced apoptosis in human lymphoma is associated with poor prognosis and complex genetic B -cell chronic leukemia ” , British Journal of Haematology , 117 : alterations. " 842 - 851 ( 2002 ) . Li et al. , British Journal of Pharmacology , 160 ( 6 ) :1352 - 1361 ( 2010 ) . Wang et al . , “ The study of resveratrol by modulating SATA3 on “ 2 , 3 ' , 4 , 4 , 5 ' - Pentamethoxy -trans - stilbene, a resveratrol derivative , acute myeloblastic leukemia ” , Chinese Pharmacological Bulletin , inhibits colitis -associated colorectal carcinogenesis in mice. " 26 ( 3 ) : 346 -352 ( 2010 ) . Liu et al. , Molecular and Cellular Biochemistry , 308 ( 1 - 2 ) : 117 -125 Li et al. , “ Crystal Struture of an Archaeal Rad51 Homologue in ( 2007 ) . " Anion exchanger inhibitor DIDS induces human poorly Complex with a Metatungstate Inhibitor” , Biochemistry 48 (29 ) :6805 differentiated malignant hepatocellular carcinoma HA22T cell apop 6810 ( 2009 ) . tosis . " Froeyen et al ., “ RNA as a target for drug design , the example of Palacios, F . et al . “ High expression of AID and active class switch Tat - TAR interaction .” Current Topics in Medicinal chemistry 2 ( 10 ) :1123 recombination might account for a more aggressive disease in 1145 ( 2002 ) . unmutated CLL patients : link with an activated microenvironment Gunosewoyo et al. , “ Molecular probes for P2X7 receptor studies .” in CLL disease , ” Blood , 115 ( 22 ) : 4488 - 4496 ( Jun . 3 , 2010 ) . doi: Current Medicinal Chemistry 14 ( 14 ) : 1505 - 1523 ( 2007 ) . 10 . 1182 /blood - 2009 - 12 - 257758 . Epub Mar . 16 , 2010 . Soo et al. “ Visible light- induced hole injection into rectifying Roberti et al ., “ Synthesis and biological evaluation of resveratrol molecular wires anchored on Co304 and SiO2 nanoparticles . ” and analogues as apoptosis - inducing agents . ” J . Med . Chem . Journal of the American Chemical Society 134 (41 ) : 17104 - 17116 46 ( 16 ) :3546 -54 (2003 ) . ( 2012 ) . Yu et al . , “ Convenient preparation of trans -arylalkenes via pal Thompson et al ., “ Inhibitors of the glutamate vesicular transporter ladium ( IO ) - catalyzed isomerization of cis -arylalkenes . Meier et al ., ( VGLUT) . ” Current Medicinal Chemistry 12 ( 18 ) : 2041 - 2056 (2005 ) . Bis ( stilbenyl) squaraines -Novel Pigments with Extended Conjuga Wrobel et al . “ Synthesis of (bis ) sulfonic acid , (bis ) benzamides as tion .” Tetrahedron Lett ., 37 ( 8 ) : 1191- 1194 ( 1996 ) . J . Org . Chem . follicle - stimulating hormone (FSH ) antagonists . " Bioorganic & 67 ( 13 ) :4627 - 29 ( 2002 ) . Medicinal Chemistry 10 ( 3 ) :639 - 656 ( 2002 ) . Solladie et al. , “ A re -investigation of resveratrol synthesis by Eckermann et al. , “ Stilbenecarboxylate biosynthesis : a new function Perkins reaction . Application to the synthesis of aryl cinnamic in the family of chalcone synthase -related proteins. ” Phytochemistry acids. " Tetrahedron 59 : 3315 -3321 (2003 ) . 62 ( 3 ): 271 - 286 ( 2003 ) . Eddarir et al. , “ Fluorinated resveratrol and pterostilbene .” Tetrahe dron Lett ., 42 : 9127 - 9130 ( 2001 ) . * cited by examiner atent Feb . 19 , 2019 Sheet 1 of 27 US 10 ,207 , 988 B2 WT V cococococok WT Ctrl . 22000 .: 0 , Trp534- XKD W WWWXWWW: eGFP+cells (normalized) 2 00000000000000000000000000000000000000000000000000000000000000000000000 Non Act FIG . 1 U . S . Patent Feb . 19 , 2019 Sheet 2 of 27 US 10 ,207 , 988 B2 Aicda+ / + T Aicda / cocococococoooo.oooooooooooo eGFptcells (normalized). or WWWWWWWWWW ooooooooooooooooooooooo Zoooooooooooooooooooooooooooooooooooooooooooooo