Title:
SENOLYTIC AND ANTIINFLAMMATORY PRODRUGS AND METHODS OF USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2021/057061
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 selectivelv 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)
ZHAO JINGJING (CN)
DONG JIEBIN (CN)
LI HONGGANG (CN)
LUO TUOPING (CN)
CAI YUSHENG (CN)
ZHOU HUANHUAN (CN)
ZHU YINHUA (CN)
ZHAO JINGJING (CN)
DONG JIEBIN (CN)
LI HONGGANG (CN)
Application Number:
PCT/CN2020/092933
Publication Date:
April 01, 2021
Filing Date:
May 28, 2020
Export Citation:
Assignee:
UNIV BEIJING (CN)
International Classes:
C07H19/073; A61K31/7068; A61P29/00; A61P39/00
Domestic Patent References:
WO2017189553A1 | 2017-11-02 | |||
WO2009016647A1 | 2009-02-05 |
Foreign References:
US5561119A | 1996-10-01 | |||
US20180094015A1 | 2018-04-05 |
Other References:
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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, vol. 155, 20 November 2017 (2017-11-20), 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, vol. 3, no. 5, 5 February 2008 (2008-02-05), 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, vol. 11, no. 22, 11 October 2016 (2016-10-11), 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, 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 Galβ1-4GlcNAcβ-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, vol. 155, 20 November 2017 (2017-11-20), 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, vol. 3, no. 5, 5 February 2008 (2008-02-05), 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, vol. 11, no. 22, 11 October 2016 (2016-10-11), 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, 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 Galβ1-4GlcNAcβ-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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