Title:
SENOLYTIC AND ANTIINFLAMMATORY PRODRUGS AND METHODS OF USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2021/056996
Kind Code:
A1
Abstract:
Senolytic and anti-inflammatory prodrugs are provided, which are designed from a cytotoxic agent, by chemically modifying the cytotoxic agent to incorporate a site cleavable by SA-β-gal following delivery of the prodrug in vivo, to release the active parent drug. The prodrug includes a galactose-based moiety, which is preferably acetylated, and benzyl oxy carboxy group and a cytotoxic agent moiety. The selenolytic prodrug is used to selectively kill one or more senescent cells and/or reduce an acute or chronic inflammatory response in a subject in need thereof, by administering to the subject therapeutically effective amount of the senolytic prodrugs. The disclosed compositions can be used to reduce one or more symptoms associated with a Senescence-associated disease or disorder or an inflammatory disorder, for example, a virus-mediated inflammation, in a subject.
Inventors:
DENG HONGKUI (CN)
LUO TUOPING (CN)
CAI YUSHENG (CN)
ZHOU HUANHUAN (CN)
ZHU YINHUA (CN)
LUO TUOPING (CN)
CAI YUSHENG (CN)
ZHOU HUANHUAN (CN)
ZHU YINHUA (CN)
Application Number:
PCT/CN2020/081133
Publication Date:
April 01, 2021
Filing Date:
March 25, 2020
Export Citation:
Assignee:
UNIV BEIJING (CN)
International Classes:
C07H19/073; A61K31/7068; A61P29/00; A61P39/00
Domestic Patent References:
| WO2017189553A1 | 2017-11-02 | |||
| WO2017189553A1 | 2017-11-02 | |||
| WO2009016647A1 | 2009-02-05 |
Foreign References:
| US5561119A | 1996-10-01 | |||
| US20180094015A1 | 2018-04-05 |
Other References:
AJIT K GHOSH , SAEED KHAN , FRANK MARINI , J ARLY NELSON , DAVID FARQUHAR: "A daunorubicin beta-galactoside prodrug for use in conjunction with gene-directed enzyme prodrug therapy", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM , NL, vol. 41, no. 25, 19 June 2000 (2000-06-19), Amsterdam , NL, pages 4871 - 4874, XP004205673, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(00)00742-5
SHARMA AMIT; KIM EUN-JOONG; SHI HU; LEE JIN YONG; CHUNG BONG GEUN; KIM JONG SEUNG: "Development of a theranostic prodrug for colon cancer therapy by combining ligand-targeted delivery and enzyme-stimulated activation", BIOMATERIALS, ELSEVIER, AMSTERDAM, NL, vol. 155, 20 November 2017 (2017-11-20), AMSTERDAM, NL, pages 145 - 151, XP085320144, ISSN: 0142-9612, DOI: 10.1016/j.biomaterials.2017.11.019
AHMED KAMAL, VENKATESH TEKUMALLA, ANITA KRISHNAN, MANIKA PAL-BHADRA, UTPAL BHADRA: "Development of Pyrrolo[2,1-c][1,4]benzodiazepine beta‐Galactoside Prodrugs for Selective Therapy of Cancer by ADEPT and PMT", CHEMMEDCHEM COMMUNICATIONS, WILEY-VCH, DE, vol. 3, no. 5, 5 February 2008 (2008-02-05), DE, pages 794 - 802, XP002651397, ISSN: 1860-7179, DOI: 10.1002/cmdc.200700328
HANTHO JOSEPH D., STRAYER TIMOTHY A., NIELSEN AMY E., MANCINI ROCK J.: "An Enzyme-Directed Imidazoquinoline for Cancer Immunotherapy", CHEMMEDCHEM COMMUNICATIONS, WILEY-VCH, DE, vol. 11, no. 22, 11 October 2016 (2016-10-11), DE, pages 2496 - 2500, XP055793846, ISSN: 1860-7179, DOI: 10.1002/cmdc.201600443
HEIKO J. SCHUSTER, BIRGIT KREWER, J. MARIAN VON HOF, KIANGA SCHMUCK, INGRID SCHUBERTH, FRAUKE ALVES, LUTZ F. TIETZE: "Synthesis of the first spacer containing prodrug of a duocarmycin analogue and determination of its biological activity", ORGANIC & BIOMOLECULAR CHEMISTRY, ROYAL SOCIETY OF CHEMISTRY, vol. 8, no. 8, 17 February 2010 (2010-02-17), pages 1833 - 1842, XP055019053, ISSN: 1477-0520, DOI: 10.1039/b925070k
SARKAR ARUN K, FRITZ TIMOTHY A, TAYLOR WILLIAM H, ESKO JEFFREY D, ROBBINS PHILLIPS W: "Disaccharide uptake and priming in animal cells: Inhibition of sialyl Lewis X by acetylated GalIl1-4GlcNAcI3-O-naphthalenemethanol", PNAS, vol. 92, 11 April 1995 (1995-04-11), pages 3323 - 3327, XP055793850, DOI: 10.1073/pnas.92.8.3323
SHARMA AMIT; KIM EUN-JOONG; SHI HU; LEE JIN YONG; CHUNG BONG GEUN; KIM JONG SEUNG: "Development of a theranostic prodrug for colon cancer therapy by combining ligand-targeted delivery and enzyme-stimulated activation", BIOMATERIALS, ELSEVIER, AMSTERDAM, NL, vol. 155, 20 November 2017 (2017-11-20), AMSTERDAM, NL, pages 145 - 151, XP085320144, ISSN: 0142-9612, DOI: 10.1016/j.biomaterials.2017.11.019
AHMED KAMAL, VENKATESH TEKUMALLA, ANITA KRISHNAN, MANIKA PAL-BHADRA, UTPAL BHADRA: "Development of Pyrrolo[2,1-c][1,4]benzodiazepine beta‐Galactoside Prodrugs for Selective Therapy of Cancer by ADEPT and PMT", CHEMMEDCHEM COMMUNICATIONS, WILEY-VCH, DE, vol. 3, no. 5, 5 February 2008 (2008-02-05), DE, pages 794 - 802, XP002651397, ISSN: 1860-7179, DOI: 10.1002/cmdc.200700328
HANTHO JOSEPH D., STRAYER TIMOTHY A., NIELSEN AMY E., MANCINI ROCK J.: "An Enzyme-Directed Imidazoquinoline for Cancer Immunotherapy", CHEMMEDCHEM COMMUNICATIONS, WILEY-VCH, DE, vol. 11, no. 22, 11 October 2016 (2016-10-11), DE, pages 2496 - 2500, XP055793846, ISSN: 1860-7179, DOI: 10.1002/cmdc.201600443
HEIKO J. SCHUSTER, BIRGIT KREWER, J. MARIAN VON HOF, KIANGA SCHMUCK, INGRID SCHUBERTH, FRAUKE ALVES, LUTZ F. TIETZE: "Synthesis of the first spacer containing prodrug of a duocarmycin analogue and determination of its biological activity", ORGANIC & BIOMOLECULAR CHEMISTRY, ROYAL SOCIETY OF CHEMISTRY, vol. 8, no. 8, 17 February 2010 (2010-02-17), pages 1833 - 1842, XP055019053, ISSN: 1477-0520, DOI: 10.1039/b925070k
SARKAR ARUN K, FRITZ TIMOTHY A, TAYLOR WILLIAM H, ESKO JEFFREY D, ROBBINS PHILLIPS W: "Disaccharide uptake and priming in animal cells: Inhibition of sialyl Lewis X by acetylated GalIl1-4GlcNAcI3-O-naphthalenemethanol", PNAS, vol. 92, 11 April 1995 (1995-04-11), pages 3323 - 3327, XP055793850, DOI: 10.1073/pnas.92.8.3323
Attorney, Agent or Firm:
CHINA SCIENCE PATENT & TRADEMARK AGENT LTD. (CN)
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