DOCSLIB.ORG

Arylquinoline and Analog Compounds and Use Thereof to Treat Cancer David S

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

University of Kentucky UKnowledge Molecular and Cellular Biochemistry Faculty Molecular and Cellular Biochemistry Patents 1-23-2018 Arylquinoline and Analog Compounds and Use Thereof to Treat Cancer David S. Watt University of Kentucky, [email protected] Chunming Liu University of Kentucky, [email protected] Vivek M. Rangnekar University of Kentucky, [email protected] Vitaliy M. Sviripa University of Kentucky, [email protected] Ravshan Burikhanov University of Kentucky, [email protected] See next page for additional authors Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/biochem_patents Part of the Medical Biochemistry Commons Recommended Citation Watt, David S.; Liu, Chunming; Rangnekar, Vivek M.; Sviripa, Vitaliy M.; Burikhanov, Ravshan; and Zhang, Wen, "Arylquinoline and Analog Compounds and Use Thereof to Treat Cancer" (2018). Molecular and Cellular Biochemistry Faculty Patents. 25. https://uknowledge.uky.edu/biochem_patents/25 This Patent is brought to you for free and open access by the Molecular and Cellular Biochemistry at UKnowledge. It has been accepted for inclusion in Molecular and Cellular Biochemistry Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Authors David S. Watt, Chunming Liu, Vivek M. Rangnekar, Vitaliy M. Sviripa, Ravshan Burikhanov, and Wen Zhang This patent is available at UKnowledge: https://uknowledge.uky.edu/biochem_patents/25 I IIIII IIIIIIII Ill lllll lllll US009873670B2lllll lllll lllll lllll lllll lllll 111111111111111111 c12) United States Patent (IO) Patent No.: US 9,873,670 B2 Watt et al. (45) Date of Patent: Jan.23,2018 (54) ARYLQUINOLINE AND ANALOG C07D 495/04 (2006.01) COMPOUNDS AND USE THEREOF TO C07D 2151227 (2006.01) TREAT CANCER C07D 215/36 (2006.01) (52) U.S. Cl. (71) Applicant: UNIVERSITY OF KENTUCKY CPC ............ C07D 215/38 (2013.01); A61K 31147 RESEARCH FOUNDATION, (2013.01); C07D 215/06 (2013.01); C07D Lexington, KY (US) 2151227 (2013.01); C07D 215/36 (2013.01); C07D 495/04 (2013.01) (72) Inventors: David S. Watt, Lexington, KY (US); (58) Field of Classification Search Chunming Liu, Lexington, KY (US); CPC ............................ C07D 215/38; C07D 215/06 Vivek Rangnekar, Nicholasville, KY See application file for complete search history. (US); Vitaliy M. Sviripa, Lexington, KY (US); Ravshan Burikhanov, (56) References Cited Lexington, KY (US); Wen Zhang, U.S. PATENT DOCUMENTS Lexington, KY (US) 2007/0077644 Al 4/2007 Yoshio (73) Assignee: University of Kentucky Research Foundation, Lexington, KY (US) FOREIGN PATENT DOCUMENTS ( *) Notice: Subject to any disclaimer, the term ofthis WO 2009/127417 Al 10/2009 patent is extended or adjusted under 35 U.S.C. 154(b) by O days. OTHER PUBLICATIONS (21) Appl. No.: 15/036,916 Walser et al., J. Heterocyclic Chemistry (1975), 12(2), 351-8. Mphahlele et al., Molecules (2011), 16, 8958-8972. (22) PCT Filed: Nov. 21, 2014 L. Fu et al., "Novel and efficient synthesis of substituted quinoline- 1-oxides and the complex compounds SnL2Cl2 (L�2- aminoquinoline-l-oxides) with the aid of stannous chloride," Tet­ (86) PCT No.: PCT/US2014/066796 rahedron 68 (2012), 7782-7786. § 371 (c)(l), Burikhanov et al., "Arylquins target vimentin to triggar Par-4 (2) Date: May 16, 2016 secretion for tumor cell apoptosis," Nature Chemical Biology, Sep. 14, 2014, vol. 10, No. 11, pp. 924-926. International Search Report and Written Opinion issued in Appli­ (87) PCT Pub. No.: W02015/077550 cation No. PCT/US2014/066796 dated Feb. 15, 2015. PCT Pub. Date: May 28, 2015 Primary Examiner - Samira Jean-Louis (65) Prior Publication Data (74) Attorney, Agent, or Firm - McDermott Will & Emery LLP US 2016/0280652 Al Sep. 29, 2016 (57) ABSTRACT Related U.S. Application Data The subject technology relates to arylquinoline compounds (60) Provisional application No. 61/907,817, filed on Nov. and their use for treating cancer or cancer metastasis. The 22, 2013. compounds of the subject technology promote cells to secrete a pro-apoptotic tumor suppressor, i.e., prostate apop­ (51) Int. Cl. tosis response-4 (Par-4), which in tum promote apoptosis in C07D 215/38 (2006.01) cancer cells or metastatic cells. C07D 215/06 (2006.01) A61K 31147 (2006.01) 13 Claims, 5 Drawing Sheets U.S. Patent Jan.23,2018 Sheet 1 of 5 US 9,873,670 B2 X = ortho-F, Y = NMe (Arylquin 1) = = 2 X meta-F, Y NMe2 (Arylquin 2) = = N 3 X para-F, Y Me2 (Aryl1uin ) X = H, Y = NMe2 (Arylquin l X = ortho-F, Y = H (Arylquin 8) ..__...e, f = 4 Z O (Arylquin ) .......i-- 6 Z = S (Arylquin 5) , c Arylquin : I di H N 0 0 NH S� ri2 \12 ri2 O Biotinylated Arylquin 9 O ° 3 b, Legend of reagents: a, arylacetonitrile, terl-BuOK,DMF, 90 C, -4h; ° 2(2'­ c, fluorophenyl)acetyl chloride, Et3N, reflux2h and then K2C03, DMF, 90 C, 4h; 2,4-bis(4- methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (Lawesson's reagent), dioxane, d, 0 reflux 5h; (+)-biotinyl-iodoacetamidyl-°3,6-dioxaoctanediamine, K2C 3, DMF, 12h; e, POCl3, reflux, 3h; f,Zn, CH3C02H, 75 C, 1 h. FIG.1 U.S. Patent Jan.23,2018 Sheet 2 of 5 US 9,873,670 B2 80 ** t,. PC-3 60 D H1299 -� o HOP92 g- 40 ¢ HEL CLco 2f2- 20 o ...........---� V 0.5 1 10 [Arylquin 1] (µM) oPC-3 MM2 8 11H 6 80 oLLC-1 80 0 4 0 ** 11 DU145 oA549 ** oWTMEF a LNCaP U) 6 11KP7B 6 -� 60 o BEC - 0 -� 0 v ** HEL � a p53·/- MEF PrE 40 o ** g-40 i40 o PrS ** JCL ::t * � 2f2- 20 � 20 2f2- 20 o�---.---.---, V 0.5 1 10 V 0.5 1 10 V 0.5 1 10 Arylquin 1 (µM) Arylquin 1 (µM) Arylquin 1 (µM) FIG. 2 U.S. Patent Jan.23,2018 Sheet 3 of 5 US 9,873,670 B2 50 n E:'21 Vehicle � Arylquin 1 40 �=­ 30 C) '#.cu 20 10 o..U..:..t:....,;L.t:....,;L..lll....J..'--ll.ul'--ll.ulilU...J�.iL..L.;J.;U....l:....;J.;..lll....J..�L...L..(;JilU...J�.iL..L...L.l.(..L..L.l.(..L�HEL H1299 HOP92 A549 H460 PC-3 HEL H1299 HOP92 A549 H460 PC-3 Par-4-expressing Par-4-null MEFs co-culture MEFs co-culture ** n 50 ** ** r, 40 0Vehicle -�=­ 30 IZJArylquin1 C) '#.g- 20 10 o�..&.:..:.L.-L...;t;.:.i.._..i...:.i..:.;.L......L�-L..�...J..a.;4-�-L�HEL H1299 HOP92 A549 H460 No Con Par-4 Antibody PC-3 MM2 Mouse serum treatment FIG. 3 U.S. Patent Jan.23,2018 Sheet 4 of 5 US 9,873,670 B2 80 c:: KP-78 LLC-1 H460 A549 H1299 0 ** ·u5en � 60 (l) 00r-- ci.. et:: <!) 40 (l) 0 � en= (l) 0 20 �0 0 Par-4·/· + V + + + + + Par-4·/· + Aq + + + + + CM from + + Par-4 / + V + + + + + Par-4+/+ + Aq 60 KP-78 LLC-1 H460 A549 H1299 ** ** en ·u5 40 .9 ** ·.:·· =- ·.:···. :::::: =-0 �0 :{ 20 :}·.:···. 0 Par-4·/· + Aq C c c c c + CM Par-4·/· Aq + · G G G G G + + Ab· from Par-4 / + Aq c c c c c Par-4+/+ + Aq G G G G G FIG.4 U.S. Patent Jan.23,2018 Sheet 5 of 5 US 9,873,670 B2 75 ** ** c:: en ·u5 %2 =­ 5 <( Q+-=aa;;aa-----=a,,aaaaa----=aa,a=-----'=a,aaa--- Vim+/+ Vim·/- Par -4 Ab lgG Ab Vim·/- FIG. 5 US 9,873,670 B2 1 2 ARYLQUINOLINE AND ANALOG ment of cancer or for the treatment or inhibition of cancer COMPOUNDS AND USE THEREOF TO metastasis in a subject in need thereof comprising adminis­ TREAT CANCER tering to the subject an effectiveamount of the compound or a pharmaceutically acceptable salt thereof or a composition CROSS-REFERENCE TO RELATED 5 thereof. Other advantages of the subject technology include com­ APPLICATION pounds for use in promoting the secretion of Prostate Apoptosis Response-4 (PAR-4) from cells or for use in This application is a U.S. National Phase under 35 U.S.C. promoting apoptosis of a cancer cell in a subject comprising §371 oflnternational Application No. PCT/US2014/066796, administering to the subject an effective amount of an 10 filed Nov. 21, 2014, which claims the benefit of U.S. arylquinoline or analog compound or a pharmaceutically Provisional Application No. 61/907,817, filed Nov. 22, acceptable salt thereof or a composition thereof. 2013, the entire disclosures of which are hereby incorpo­ In one aspect of the subject technology, the arylquinoline rated by reference herein. is a compound according to Formula (I): STATEMENT REGARDING FEDERALLY 15 SPONSORED RESEARCH (I) This work was supported by National Center for Research Resources in a grant entitled "COBRE Center for Biomedi- cal Research Excellence" grant P20 RR020171; and NIH/ 20 NCI ROI CA60872 (to VMR). The government has certain rights in the subject technology. TECHNICAL FIELD or a pharmaceutically acceptable salt thereof; wherein n is 1, 25 2, 3, 4, 5, or 6, for each NR1 R2, R1 and R2 are independently The present invention relates to compounds that treat H, alkyl, alkoxy, aryl, heteroaryl; Ar is aryl or heteroaryl, cancer and/or treat or prevent cancer metastasis. In particu­ which can be further substituted with halogen, amino, alky­ lar, the subject technology is directed to arylquinoline com­ lamino, dialkylamino, arylalkylamino, N-oxides of dialky­ pounds and analogs thereof such as arylquinolone or aryl­ lamino, trialkylammonium, mercapto, alkylthio, alkanoyl, thioquinolone compounds, described as "arylquin" 30 nitro, nitrosyl, cyano, alkoxy, alkenyloxy, aryl, heteroaryl, compounds, that promote cells to secrete a pro-apoptotic sulfonyl, sulfonamide, CONR3R4, NR3CO(R4), NR3COO tumor suppressor, such as prostate apoptosis response-4 (R4), NR3CONR4R5 where R3, R4, R5, are independently, H, (Par-4), which promotes apoptosis in cancer cells or meta­ alkyl, aryl, heteroaryl or a fluorine; X represents halogen; m static cells.
Recommended publications
  • Synthesis and Antitumor Evaluation of Novel Bis-Triaziquone Derivatives

    Synthesis and Antitumor Evaluation of Novel Bis-Triaziquone Derivatives

    Molecules 2009, 14, 2306-2316; doi:10.3390/molecules14072306 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article Synthesis and Antitumor Evaluation of Novel Bis-Triaziquone Derivatives Cheng Hua Huang 1,3, Hsien-Shou Kuo 2, Jia-Wen Liu 3 and Yuh-Ling Lin 3,* 1 Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei, Taiwan 2 Department of Biochemistry, Taipei Medical University, 250 Wu-Hsin St. Taipei, Taiwan 3 College of Medicine, Fu-Jen Catholic University, 510 Chung Cheng Rd., Hsin-Chuang, Taipei Hsien 24205, Taiwan * Author to whom correspondence should be addressed; E-mail: [email protected] Received: 30 April 2009; in revised form: 19 June 2009 / Accepted: 23 June 2009 / Published: 29 June 2009 Abstract: Aziridine-containing compounds have been of interest as anticancer agents since late 1970s. The design, synthesis and study of triaziquone (TZQ) analogues with the aim of obtaining compounds with enhanced efficacy and reduced toxicity are an ongoing research effort in our group. A series of bis-type TZQ derivatives has been prepared and their cytotoxic activities were investigated. The cytotoxicity of these bis-type TZQ derivatives were tested on three cancer lines, including breast cancer (BC-M1), oral cancer (OEC-M1), larynx epidermal cancer (Hep2) and one normal skin fibroblast (SF). Most of these synthetic derivatives displayed significant cytotoxic activities against human carcinoma cell lines, but weak activities against SF. Among tested analogues the bis-type TZQ derivative 1a showed lethal effects on larynx epidermal carcinoma cells (Hep2), with an LC50 value of 2.02 M, and also weak cytotoxic activity against SF cells with an LC50 value over 10 M for 24 hr treatment.
  • C-1027, a Radiomimetic Enediyne Anticancer Drug, Preferentially Targets Hypoxic Cells

    C-1027, a Radiomimetic Enediyne Anticancer Drug, Preferentially Targets Hypoxic Cells

    Research Article C-1027, A Radiomimetic Enediyne Anticancer Drug, Preferentially Targets Hypoxic Cells Terry A. Beerman,1 Loretta S. Gawron,1 Seulkih Shin,1 Ben Shen,2 and Mary M. McHugh1 1Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York;and 2Division of Pharmaceutical Sciences, University of Wisconsin National Cooperative Drug Discovery Group, and Department of Chemistry, University of Wisconsin, Madison, Wisconsin Abstract identified primarily from studies with neocarzinostatin (NCS), a The hypoxic nature of cells within solid tumors limits the holo-form drug, consisting of an apoprotein carrier and an active efficacy of anticancer therapies such as ionizing radiation and chromophore, and was assumed to be representative of all agents conventional radiomimetics because their mechanisms re- in this class (11). The NCS chromophore contains a bicyclic quire oxygen to induce lethal DNA breaks. For example, the enediyne that damages DNA via a Myers-Saito cycloaromatization conventional radiomimetic enediyne neocarzinostatin is 4- reaction, resulting in a 2,6-indacene diradical structure capable of fold less cytotoxic to cells maintained in low oxygen (hypoxic) hydrogen abstractions from deoxyribose (12, 13). Subsequent to compared with normoxic conditions. By contrast, the ene- generation of a sugar radical, reaction with oxygen quickly and diyne C-1027 was nearly 3-fold more cytotoxic to hypoxic than efficiently leads to formation of hydroxyl radicals that induce to normoxic cells. Like other radiomimetics, C-1027 induced DSBs/SSBs at a 1:5 ratio. The more recently discovered holo-form DNA breaks to a lesser extent in cell-free, or cellular hypoxic, enediyne C-1027 (Fig.
  • Journal of Pharmacology and Experimental Therapeutics

    Journal of Pharmacology and Experimental Therapeutics

    Journal of Pharmacology and Experimental Therapeutics Molecular Determinants of Ligand Selectivity for the Human Multidrug And Toxin Extrusion Proteins, MATE1 and MATE-2K Bethzaida Astorga, Sean Ekins, Mark Morales and Stephen H Wright Department of Physiology, University of Arizona, Tucson, AZ 85724, USA (B.A., M.M., and S.H.W.) Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay-Varina NC 27526, USA (S.E.) Supplemental Table 1. Compounds selected by the common features pharmacophore after searching a database of 2690 FDA approved compounds (www.collaborativedrug.com). FitValue Common Name Indication 3.93897 PYRIMETHAMINE Antimalarial 3.3167 naloxone Antidote Naloxone Hydrochloride 3.27622 DEXMEDETOMIDINE Anxiolytic 3.2407 Chlordantoin Antifungal 3.1776 NALORPHINE Antidote Nalorphine Hydrochloride 3.15108 Perfosfamide Antineoplastic 3.11759 Cinchonidine Sulfate Antimalarial Cinchonidine 3.10352 Cinchonine Sulfate Antimalarial Cinchonine 3.07469 METHOHEXITAL Anesthetic 3.06799 PROGUANIL Antimalarial PROGUANIL HYDROCHLORIDE 100MG 3.05018 TOPIRAMATE Anticonvulsant 3.04366 MIDODRINE Antihypotensive Midodrine Hydrochloride 2.98558 Chlorbetamide Antiamebic 2.98463 TRIMETHOPRIM Antibiotic Antibacterial 2.98457 ZILEUTON Antiinflammatory 2.94205 AMINOMETRADINE Diuretic 2.89284 SCOPOLAMINE Antispasmodic ScopolamineHydrobromide 2.88791 ARTICAINE Anesthetic 2.84534 RITODRINE Tocolytic 2.82357 MITOBRONITOL Antineoplastic Mitolactol 2.81033 LORAZEPAM Anxiolytic 2.74943 ETHOHEXADIOL Insecticide 2.64902 METHOXAMINE Antihypotensive Methoxamine
  • California Proposition 65 Toxicity List

    California Proposition 65 Toxicity List

    STATE OF CALIFORNIA ENVIRONMENTAL PROTECTION AGENCY OFFICE OF ENVIRONMENTAL HEALTH HAZARD ASSESSMENT SAFE DRINKING WATER AND TOXIC ENFORCEMENT ACT OF 1986 CHEMICALS KNOWN TO THE STATE TO CAUSE CANCER OR REPRODUCTIVE TOXICITY 4-Mar-05 The Safe Drinking Water and Toxic Enforcement Act of 1986 requires that the Governor revise and Chemical Type of Toxicity CAS No. Date Listed A-alpha-C (2-Amino-9H-pyrido[2,3-b]indole) cancer 26148685 1-Jan-90 Acetaldehyde cancer 75070 1-Apr-88 Acetamide cancer 60355 1-Jan-90 Acetazolamide developmental 59665 20-Aug-99 Acetochlor cancer 34256821 1-Jan-89 Acetohydroxamic acid developmental 546883 1-Apr-90 2-Acetylaminofluorene cancer 53963 1-Jul-87 Acifluorfen cancer 62476599 1-Jan-90 Acrylamide cancer 79061 1-Jan-90 Acrylonitrile cancer 107131 1-Jul-87 Actinomycin D cancer 50760 1-Oct-89 Actinomycin D developmental 50760 1-Oct-92 Adriamycin (Doxorubicin hydrochloride) cancer 23214928 1-Jul-87 AF-2;[2-(2-furyl)-3-(5-nitro-2-furyl)]acrylamide cancer 3688537 1-Jul-87 Aflatoxins cancer --- 1-Jan-88 Alachlor cancer 15972608 1-Jan-89 Alcoholic beverages, when associated with alcohol abuse cancer --- 1-Jul-88 Aldrin cancer 309002 1-Jul-88 All-trans retinoic acid developmental 302794 1-Jan-89 Allyl chloride Delisted October 29, 1999 cancer 107051 1-Jan-90 Alprazolam developmental 28981977 1-Jul-90 Altretamine developmental, male 645056 20-Aug-99 Amantadine hydrochloride developmental 665667 27-Feb-01 Amikacin sulfate developmental 39831555 1-Jul-90 2-Aminoanthraquinone cancer 117793 1-Oct-89 p -Aminoazobenzene cancer
  • Enediynes, Enyneallenes, Their Reactions, and Beyond

    Enediynes, Enyneallenes, Their Reactions, and Beyond

    Advanced Review Enediynes, enyne-allenes, their reactions, and beyond Elfi Kraka∗ and Dieter Cremer Enediynes undergo a Bergman cyclization reaction to form the labile 1,4-didehy- drobenzene (p-benzyne) biradical. The energetics of this reaction and the related Schreiner–Pascal reaction as well as that of the Myers–Saito and Schmittel reac- tions of enyne-allenes are discussed on the basis of a variety of quantum chemical and available experimental results. The computational investigation of enediynes has been beneficial for both experimentalists and theoreticians because it has led to new synthetic challenges and new computational methodologies. The accurate description of biradicals has been one of the results of this mutual fertilization. Other results have been the computer-assisted drug design of new antitumor antibiotics based on the biological activity of natural enediynes, the investigation of hetero- and metallo-enediynes, the use of enediynes in chemical synthesis and C materials science, or an understanding of catalyzed enediyne reactions. " 2013 John Wiley & Sons, Ltd. How to cite this article: WIREs Comput Mol Sci 2013. doi: 10.1002/wcms.1174 INTRODUCTION symmetry-allowed pericyclic reactions, (ii) aromatic- ity as a driving force for chemical reactions, and (iii) review on the enediynes is necessarily an ac- the investigation of labile intermediates with biradical count of intense and successful interdisciplinary A character. The henceforth called Bergman cyclization interactions of very different fields in chemistry provided deeper insight into the electronic structure involving among others organic chemistry, matrix of biradical intermediates, the mechanism of organic isolation spectroscopy, quantum chemistry, biochem- reactions, and orbital symmetry rules.
  • The Chemotherapy of Malignant Disease -Practical and Experimental Considerations

    The Chemotherapy of Malignant Disease -Practical and Experimental Considerations

    Postgrad Med J: first published as 10.1136/pgmj.41.475.268 on 1 May 1965. Downloaded from POSTGRAD. MED. J. (1965), 41,268 THE CHEMOTHERAPY OF MALIGNANT DISEASE -PRACTICAL AND EXPERIMENTAL CONSIDERATIONS JOHN MATTHIAS, M.D., M.R.C.P., F.F.A., R.C.S. Physician, The Royal Marsden Hospital, London, S.W.3. THE TERM chemotherapy was introduced by positively charged alkyl (CH2) radicles of Ehrlich to describe the specific and effective the agent. treatment of infectious disease by chemical (a) The nitrogen mustards: mustine (HN2 substances. It is currently also applied to the 'nitrogen mustard', mechlorethamine, treatment of malignant disease. Unfortunately mustargen), trimustine (Trillekamin no aspect of tumour metabolism has been HN3), chlorambucil (Leukeran, phenyl discovered which has allowed the development butyric mustard), melphalan (Alkeran, of drugs capable of acting specifically upon the phenyl alanine mustard), uramustine malignant cell, so that cytotoxic drugs also (Uracil mustard), cyclophosphamide affect normal cells to a greater or lesser degree. (Endoxan or Cytoxan), mannomustine The most susceptible or sensitive of the normal (DegranoO). tissues are those with the highest rates of cell (b) The ethylenamines: tretamine (trie- turnover and include the haemopoietic and thanomelamine, triethylene melamine, lympho-reticular tissues, the gastro-intestinal TEM), thiotepa (triethylene thiopho- the the testis and the hair epithelium, ovary, sphoramide), triaziquone (Trenimon).by copyright. follicles. (c) The epoxides: triethyleneglycoldigly- Cancer chemotherapy may be said to encom- cidyl ether (Epodyl). pass all treatments of a chemical nature (d) The sulphonic acid esters: busulphan administered to patients with the purpose of (Myleran), mannitol myleran. restricting tumour growth or destroying tumour 2.
  • In the United States Court of Appeals for the Federal Circuit

    In the United States Court of Appeals for the Federal Circuit

    Case: 18-1959 Document: 16 Page: 1 Filed: 08/20/2018 No. 18-1959 In the United States Court of Appeals for the Federal Circuit GENENTECH, INC., APPELLANT v. HOSPIRA, INC., APPELLEE ON APPEAL FROM THE UNITED STATES PATENT AND TRADEMARK OFFICE PATENT TRIAL AND APPEAL BOARD IN NO. IPR2016-01771 BRIEF OF APPELLANT GENENTECH, INC. PAUL B. GAFFNEY ADAM L. PERLMAN THOMAS S. FLETCHER WILLIAMS & CONNOLLY LLP 725 Twelfth Street, N.W. Washington, DC 20005 (202) 434-5000 Case: 18-1959 Document: 16 Page: 2 Filed: 08/20/2018 CERTIFICATE OF INTEREST Pursuant to Federal Circuit Rule 47.4, undersigned counsel for appellant certifies the following: 1. The full name of the party represented by me is Genentech, Inc. 2. The name of the real party in interest represented by me is the same. 3. Genentech, Inc. is a wholly-owned subsidiary of Roche Holdings Inc. Roche Holdings Inc.’s ultimate parent, Roche Holdings Ltd, is a publicly held Swiss corporation traded on the Swiss Stock Exchange. Upon information and belief, more than 10% of Roche Holdings Ltd’s voting shares are held either directly or indirectly by Novartis AG, a publicly held Swiss corporation. 4. The following attorneys appeared for Genentech, Inc. in proceedings below or are expected to appear in this Court and are not already listed on the docket for the current case: Teagan J. Gregory and Christopher A. Suarez of Williams & Connolly LLP, 725 Twelfth Street, N.W., Washington, D.C. 20005. 5. The title and number of any case known to counsel to be pending in this or any other court or agency that will directly affect or be directly affected by this court’s decision in this pending appeal are Genentech, Inc.
  • Isolation and Characterization of a Chinese Hamster Ovary Cell Line Resistant to Bifunctional Nitrogen Mustards1

    Isolation and Characterization of a Chinese Hamster Ovary Cell Line Resistant to Bifunctional Nitrogen Mustards1

    [CANCER RESEARCH 46, 6290-6294, December 1986] Isolation and Characterization of a Chinese Hamster Ovary Cell Line Resistant to Bifunctional Nitrogen Mustards1 Craig N. Robson, Janice Alexander, Adrian L. Harris, and Ian D. Hickson2 Departmem of Clinical Oncology, University of Newcastle upon Tyne, The Royal Victoria Infirmary, Newcastle upon Tyne, NEI 4LP, United Kingdom ABSTRACT mustards, is collaterally sensitive to nitrosoureas (10), despite the fact that both these classes of agent generate DNA inter- A drug-resistant derivative of a Chinese hamster ovary cell line has strand cross-links. been generated by chronic exposure to progressively higher concentra Although chlorambucil is widely used in the curative therapy tions of chlorambucil. The cells exhibit greater than 20-fold resistance of Hodgkin's disease (11), in modified cyclophosphamide-meth- to the cytotoxic effects of chlorambucil and comparable levels of cross- resistance to mechlorethamine and melphalan. These drugs all belong to otrexate-5-fluorouracil protocols for breast cancer (12), in ovar a class of bifunctional alkylating agents which generate DNA cross-links ian cancer (13), and in small cell lung cancer (14), cell lines by reaction at the N-7 position of guanine. However, no resistance is isolated on the basis of chlorambucil resistance have rarely been observed to several other drugs which possess a similar mechanism of reported (15). action, to en-platinum (Mamminedichloride or to bischloroethylnitrosou- Here, we describe the isolation of a CHO3 cell line which rea and mitomycin C, which cross-link DNA via the O6 position of exhibits elevated levels of resistance to the cytotoxic effects of guaninc.
  • Pdf; Chi 2015 DPP Air in Cars.Pdf; Dodson 2014 DPP Dust CA.Pdf; Kasper-Sonnenberg 2014 Phth Metabolites.Pdf; EU Cosmetics Regs 2009.Pdf

    Pdf; Chi 2015 DPP Air in Cars.Pdf; Dodson 2014 DPP Dust CA.Pdf; Kasper-Sonnenberg 2014 Phth Metabolites.Pdf; EU Cosmetics Regs 2009.Pdf

    Bouge, Cathy (ECY) From: Nancy Uding <[email protected]> Sent: Friday, January 13, 2017 10:24 AM To: Steward, Kara (ECY) Cc: Erika Schreder Subject: Comments re. 2016 CSPA Rule Update - DPP Attachments: DPP 131-18-0 exposure.pdf; Chi 2015 DPP air in cars.pdf; Dodson 2014 DPP dust CA.pdf; Kasper-Sonnenberg 2014 phth metabolites.pdf; EU Cosmetics Regs 2009.pdf Please accept these comments from Toxic-Free Future concerning the exposure potential of DPP for consideration during the 2016 CSPA Rule update. Regards, Nancy Uding -- Nancy Uding Grants & Research Specialist Toxic-Free Future 206-632-1545 ext.123 http://toxicfreefuture.org 1 JES-00888; No of Pages 9 JOURNAL OF ENVIRONMENTAL SCIENCES XX (2016) XXX– XXX Available online at www.sciencedirect.com ScienceDirect www.elsevier.com/locate/jes Determination of 15 phthalate esters in air by gas-phase and particle-phase simultaneous sampling Chenchen Chi1, Meng Xia1, Chen Zhou1, Xueqing Wang1,2, Mili Weng1,3, Xueyou Shen1,4,⁎ 1. College of Environmental & Resource Sciences, Zhejiang University, Hangzhou 310058, China 2. Zhejiang National Radiation Environmental Technology Co., Ltd., Hangzhou 310011, China 3. School of Environmental and Resource Sciences, Zhejiang Agriculture and Forestry University, Hangzhou 310058, China 4. Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou 310058, China ARTICLE INFO ABSTRACT Article history: Based on previous research, the sampling and analysis methods for phthalate esters (PAEs) Received 24 December 2015 were improved by increasing the sampling flow of indoor air from 1 to 4 L/min, shortening the Revised 14 January 2016 sampling duration from 8 to 2 hr.
  • Re-Visiting Hypersensitivity Reactions to Taxanes: a Comprehensive Review

    Re-Visiting Hypersensitivity Reactions to Taxanes: a Comprehensive Review

    Clinic Rev Allerg Immunol DOI 10.1007/s12016-014-8416-0 Re-visiting Hypersensitivity Reactions to Taxanes: A Comprehensive Review Matthieu Picard & Mariana C. Castells # Springer Science+Business Media New York 2014 Abstract Taxanes (a class of chemotherapeutic agents) Keywords Taxane . Paclitaxel . Taxol . Docetaxel . are an important cause of hypersensitivity reactions Taxotere . Nab-paclitaxel . Abraxane . Cabazitaxel . (HSRs) in cancer patients. During the last decade, the Chemotherapy . Hypersensitivity . Allergy . Skin test . development of rapid drug desensitization has been key Desensitization . Challenge . Diagnosis . Review . IgE . to allow patients with HSRs to taxanes to be safely re- Complement . Mechanism treated although the mechanisms of these HSRs are not fully understood. Earlier studies suggested that solvents, such as Cremophor EL used to solubilize paclitaxel, Introduction were responsible for HSRs through complement activa- tion, but recent findings have raised the possibility that Hypersensitivity reactions (HSRs) to chemotherapy are in- some of these HSRs are IgE-mediated. Taxane skin creasingly common and represent an important impediment testing, which identifies patients with an IgE-mediated to the care of cancer patients as they may entail serious sensitivity, appears as a promising diagnostic and risk consequences and prevent patients from being treated with stratification tool in the management of patients with the most efficacious agent against their cancer [1]. During the HSRs to taxanes. The management of patients following last decade, different groups have developed rapid drug de- a HSR involves risk stratification and re-exposure could sensitization (RDD) protocols that allow the safe re- be performed either through rapid drug desensitization introduction of a chemotherapeutic agent to which a patient or graded challenge based on the severity of the initial is allergic, and their use have recently been endorsed by the HSR and the skin test result.
  • Tanibirumab (CUI C3490677) Add to Cart

    Tanibirumab (CUI C3490677) Add to Cart

    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
  • BC Cancer Benefit Drug List September 2021

    BC Cancer Benefit Drug List September 2021

    Page 1 of 65 BC Cancer Benefit Drug List September 2021 DEFINITIONS Class I Reimbursed for active cancer or approved treatment or approved indication only. Reimbursed for approved indications only. Completion of the BC Cancer Compassionate Access Program Application (formerly Undesignated Indication Form) is necessary to Restricted Funding (R) provide the appropriate clinical information for each patient. NOTES 1. BC Cancer will reimburse, to the Communities Oncology Network hospital pharmacy, the actual acquisition cost of a Benefit Drug, up to the maximum price as determined by BC Cancer, based on the current brand and contract price. Please contact the OSCAR Hotline at 1-888-355-0355 if more information is required. 2. Not Otherwise Specified (NOS) code only applicable to Class I drugs where indicated. 3. Intrahepatic use of chemotherapy drugs is not reimbursable unless specified. 4. For queries regarding other indications not specified, please contact the BC Cancer Compassionate Access Program Office at 604.877.6000 x 6277 or [email protected] DOSAGE TUMOUR PROTOCOL DRUG APPROVED INDICATIONS CLASS NOTES FORM SITE CODES Therapy for Metastatic Castration-Sensitive Prostate Cancer using abiraterone tablet Genitourinary UGUMCSPABI* R Abiraterone and Prednisone Palliative Therapy for Metastatic Castration Resistant Prostate Cancer abiraterone tablet Genitourinary UGUPABI R Using Abiraterone and prednisone acitretin capsule Lymphoma reversal of early dysplastic and neoplastic stem changes LYNOS I first-line treatment of epidermal