WO2017136708A1 - Synthesis and composition of rapafucin libraries - Google Patents

Synthesis and composition of rapafucin libraries Download PDF

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Publication number
WO2017136708A1
WO2017136708A1 PCT/US2017/016481 US2017016481W WO2017136708A1 WO 2017136708 A1 WO2017136708 A1 WO 2017136708A1 US 2017016481 W US2017016481 W US 2017016481W WO 2017136708 A1 WO2017136708 A1 WO 2017136708A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
alkyl
alkenyl
alkynyl
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PCT/US2017/016481
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English (en)
French (fr)
Inventor
Jun Liu
Jingxin Wang
Zufeng Guo
Sam Hong
Wukun LIU
Hanjing Peng
Manisha Das
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Johns Hopkins University
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Johns Hopkins University
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Publication date
Priority to AU2017214550A priority Critical patent/AU2017214550B2/en
Priority to JP2018540102A priority patent/JP6891183B2/ja
Priority to MX2018009405A priority patent/MX2018009405A/es
Priority to US16/074,017 priority patent/US10662220B2/en
Priority to CN201780010182.2A priority patent/CN108713028B/zh
Priority to CA3013589A priority patent/CA3013589A1/en
Application filed by Johns Hopkins University filed Critical Johns Hopkins University
Priority to EP17748264.3A priority patent/EP3411413A4/en
Publication of WO2017136708A1 publication Critical patent/WO2017136708A1/en
Anticipated expiration legal-status Critical
Priority to US16/590,087 priority patent/US11066416B2/en
Priority to US17/332,331 priority patent/US11945827B2/en
Priority to US18/584,888 priority patent/US20240239810A1/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
    • C07K17/02—Peptides being immobilised on, or in, an organic carrier
    • C07K17/08—Peptides being immobilised on, or in, an organic carrier the carrier being a synthetic polymer
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2570/00—Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders

Definitions

  • the invention relates generally to hybrid cyclic molecules, and more specifically to hybrid cyclic libraries based on the immunophilin ligand family of natural products FK506 and rapamycyin.
  • FK506 and rapamycin are approved immunosuppressive drugs with important biological activities. Both have been shown to inhibit T cell activation, albeit with distinct mechanisms.
  • rapamycin has been shown to have strong anti-proliferative activity.
  • FK506 and rapamycin share an extraordinary mode of action; they act by recruiting an abundant and ubiquitously expressed cellular protein, the prolyl cis-trans isomerase FKBP, and the binary complexes subsequently bind to and allosterically inhibit their target proteins calcineurin and mTOR, respectively. Structurally, FK506 and rapamycin share a similar FKBP-binding domain but differ in their effector domains.
  • One embodiment of the present invention is to provide a compound of the following structure:
  • R 1 and R 3 can independently be any of the following compounds:
  • R 2 and R 4 can independently be any of the following compounds:
  • Another embodiment of the present invention is to provide a compound of the following structure:
  • R 1 , R 2 , R 3 and R 4 are selected from the same groupings of compounds listed above.
  • Another embodiment of the present invention is to provide a compound that includes A15-34-2, A15-39-1, A15-39-2, A15-39-4, A15-39-6, A15-39-8, A15-39-15, A15- 40-2, A15-40-4, A15-40-15, E15-32-2, E15-33-1, E15-33-2, E15-34-1, E15-34-2, E15-39-1, E15-39-2, E15-39-5, E15-40-2, E15-40-4, E15-S-19, E15-S-21, and E15-S-22.
  • Another embodiment of the present invention is to provide synthetic methods as outlined in the“Detailed Description of the Invention” for producing a Rapafucin library.
  • Figure 1 Number of compounds in library. DETAILED DESCRIPTION OF THE INVENTION
  • R 1 and R 3 in Scheme 1 are amino acids selected from the following group of amino acids:
  • R 2 and R 4 in Scheme 1 are amino acids selected from the following group of amino acids:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Biotechnology (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oncology (AREA)
  • Hospice & Palliative Care (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US2017/016481 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries Ceased WO2017136708A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EP17748264.3A EP3411413A4 (en) 2016-02-04 2017-02-03 SYNTHESIS AND COMPOSITION OF RAPAFUCINE LIBRARIES
JP2018540102A JP6891183B2 (ja) 2016-02-04 2017-02-03 ラパフシン・ライブラリの合成と組成物
MX2018009405A MX2018009405A (es) 2016-02-04 2017-02-03 Sintesis y composicion de bibliotecas de rapafucina.
US16/074,017 US10662220B2 (en) 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries
CN201780010182.2A CN108713028B (zh) 2016-02-04 2017-02-03 rapafucin文库的合成和组合物
AU2017214550A AU2017214550B2 (en) 2016-02-04 2017-02-03 Synthesis and composition of Rapafucin libraries
CA3013589A CA3013589A1 (en) 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries
US16/590,087 US11066416B2 (en) 2016-02-04 2019-10-01 Rapafucin derivative compounds and methods of use thereof
US17/332,331 US11945827B2 (en) 2016-02-04 2021-05-27 Rapafucin derivative compounds and methods of use thereof
US18/584,888 US20240239810A1 (en) 2016-02-04 2024-02-22 Rapafucin derivative compounds and methods of use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662291437P 2016-02-04 2016-02-04
US62/291,437 2016-02-04

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/074,017 A-371-Of-International US10662220B2 (en) 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries
US16/590,087 Continuation-In-Part US11066416B2 (en) 2016-02-04 2019-10-01 Rapafucin derivative compounds and methods of use thereof

Publications (1)

Publication Number Publication Date
WO2017136708A1 true WO2017136708A1 (en) 2017-08-10

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PCT/US2017/016481 Ceased WO2017136708A1 (en) 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries

Country Status (8)

Country Link
US (1) US10662220B2 (enExample)
EP (1) EP3411413A4 (enExample)
JP (2) JP6891183B2 (enExample)
CN (1) CN108713028B (enExample)
AU (1) AU2017214550B2 (enExample)
CA (1) CA3013589A1 (enExample)
MX (1) MX2018009405A (enExample)
WO (1) WO2017136708A1 (enExample)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018225864A1 (ja) * 2017-06-09 2018-12-13 中外製薬株式会社 膜透過性の高い環状ペプチド化合物、及びこれを含むライブラリ
EP3411032A4 (en) * 2016-02-04 2019-08-14 The Johns Hopkins University RAPADOCINES, INHIBITORS OF THE EQUILIBRATION NUCLEOSIDE TRANSPORTER 1 AND USES THEREOF
WO2021067439A1 (en) 2019-10-01 2021-04-08 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
US11066416B2 (en) 2016-02-04 2021-07-20 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
US20220372014A1 (en) * 2019-10-01 2022-11-24 The Johns Hopkins University Neuroprotective compounds and methods of use thereof
US11708391B2 (en) 2016-02-04 2023-07-25 The Johns Hopkins University Rapaglutins, novel inhibitors of GLUT and use thereof
US11891457B2 (en) 2011-12-28 2024-02-06 Chugai Seiyaku Kabushiki Kaisha Peptide-compound cyclization method
US12163134B2 (en) 2015-03-13 2024-12-10 Chugai Seiyaku Kabushiki Kaisha Modified aminoacyl-tRNA synthetase and use thereof
US12391971B2 (en) 2017-01-31 2025-08-19 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptides in cell-free translation system

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10662220B2 (en) * 2016-02-04 2020-05-26 The Johns Hopkins University Synthesis and composition of rapafucin libraries
CN120271673A (zh) * 2024-01-08 2025-07-08 重庆医科大学 一种化合物、包含其的药物组合物及其用途

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US5527907A (en) * 1993-11-19 1996-06-18 Abbott Laboratories Macrolide immunomodulators
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US6984635B1 (en) * 1998-02-13 2006-01-10 Board Of Trustees Of The Leland Stanford Jr. University Dimerizing agents, their production and use
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WO2014201405A1 (en) * 2013-06-14 2014-12-18 The Board Of Regents Of The University Of Texas System Novel allosteric inhibitors of proteasome and methods of use thereof
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US10662220B2 (en) 2016-02-04 2020-05-26 The Johns Hopkins University Synthesis and composition of rapafucin libraries

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US5527907A (en) * 1993-11-19 1996-06-18 Abbott Laboratories Macrolide immunomodulators
US20020052410A1 (en) * 1995-06-07 2002-05-02 Steiner Joseph P. Rotamase enzyme activity inhibitors
US6984635B1 (en) * 1998-02-13 2006-01-10 Board Of Trustees Of The Leland Stanford Jr. University Dimerizing agents, their production and use
US20090253732A1 (en) * 2004-08-11 2009-10-08 Biotica Technology Limited Production Of Polyketides And Other Natural Products
US20080306098A1 (en) * 2006-11-06 2008-12-11 Mutz Mitchell W Pharmacokinetics of protease inhibitors and other drugs
WO2010004304A1 (en) * 2008-06-17 2010-01-14 Biotica Technology Limited Novel compounds and methods for their production
US20140073581A1 (en) 2010-11-30 2014-03-13 The Johns Hopkins University Hybrid Cyclic Libraries and Screens Thereof
US20150018340A1 (en) * 2011-12-22 2015-01-15 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Pipecolate-diketoamides for treatment of psychiatric disorders
WO2014201405A1 (en) * 2013-06-14 2014-12-18 The Board Of Regents Of The University Of Texas System Novel allosteric inhibitors of proteasome and methods of use thereof

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11891457B2 (en) 2011-12-28 2024-02-06 Chugai Seiyaku Kabushiki Kaisha Peptide-compound cyclization method
US12415835B2 (en) 2011-12-28 2025-09-16 Chugai Seiyaku Kabushiki Kaisha Peptide-compound cyclization method
US12163134B2 (en) 2015-03-13 2024-12-10 Chugai Seiyaku Kabushiki Kaisha Modified aminoacyl-tRNA synthetase and use thereof
US11945827B2 (en) 2016-02-04 2024-04-02 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
US11066416B2 (en) 2016-02-04 2021-07-20 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
US11555054B2 (en) 2016-02-04 2023-01-17 The Johns Hopkins University Rapadocins, inhibitors of equilibrative nucleoside transporter 1 and uses thereof
US11708391B2 (en) 2016-02-04 2023-07-25 The Johns Hopkins University Rapaglutins, novel inhibitors of GLUT and use thereof
EP3782636A1 (en) * 2016-02-04 2021-02-24 The Johns Hopkins University Rapadocins, inhibitors of equilibrative nucleoside transporter 1 and uses thereof
US10774110B2 (en) 2016-02-04 2020-09-15 The Johns Hopkins University Rapadocins, inhibitors of equilibrative nucleoside transporter 1 and uses thereof
EP3411032A4 (en) * 2016-02-04 2019-08-14 The Johns Hopkins University RAPADOCINES, INHIBITORS OF THE EQUILIBRATION NUCLEOSIDE TRANSPORTER 1 AND USES THEREOF
US12391971B2 (en) 2017-01-31 2025-08-19 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptides in cell-free translation system
WO2018225864A1 (ja) * 2017-06-09 2018-12-13 中外製薬株式会社 膜透過性の高い環状ペプチド化合物、及びこれを含むライブラリ
WO2021067439A1 (en) 2019-10-01 2021-04-08 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
US20220372014A1 (en) * 2019-10-01 2022-11-24 The Johns Hopkins University Neuroprotective compounds and methods of use thereof
US20230000996A1 (en) * 2019-10-01 2023-01-05 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
EP4037702A4 (en) * 2019-10-01 2023-10-18 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof

Also Published As

Publication number Publication date
EP3411413A4 (en) 2019-09-18
JP7158532B2 (ja) 2022-10-21
CA3013589A1 (en) 2017-08-10
US20190092808A1 (en) 2019-03-28
US10662220B2 (en) 2020-05-26
JP6891183B2 (ja) 2021-06-18
MX2018009405A (es) 2018-11-09
AU2017214550A1 (en) 2018-08-16
CN108713028B (zh) 2021-12-28
AU2017214550B2 (en) 2024-03-07
EP3411413A1 (en) 2018-12-12
JP2021138726A (ja) 2021-09-16
CN108713028A (zh) 2018-10-26
JP2019510738A (ja) 2019-04-18

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