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  1. Article ; Online: Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?

    Churcher, Ian

    Journal of medicinal chemistry

    2017  Volume 61, Issue 2, Page(s) 444–452

    Abstract: Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing ... ...

    Abstract Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this Perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degradation concepts and their resulting applications to medicine discovery. The approach has the potential to bring disruptive change to drug discovery; the many potential advantages and outstanding challenges which lie ahead of this technology are discussed.
    MeSH term(s) Humans ; Drug Design ; Drug Discovery ; Molecular Targeted Therapy/methods ; Peptides/pharmacology ; Proteolysis/drug effects ; Recombinant Proteins/pharmacokinetics ; Recombinant Proteins/pharmacology ; Small Molecule Libraries/pharmacology ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
    Chemical Substances Peptides ; Recombinant Proteins ; Small Molecule Libraries ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2017-12-19
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.7b01272
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  2. Article ; Online: Reaction methodology: Speed dating for reactions.

    Churcher, Ian

    Nature chemistry

    2013  Volume 5, Issue 7, Page(s) 554–555

    MeSH term(s) Chemistry, Organic
    Language English
    Publishing date 2013-05-13
    Publishing country England
    Document type News ; Comment
    ZDB-ID 2464596-5
    ISSN 1755-4349 ; 1755-4330
    ISSN (online) 1755-4349
    ISSN 1755-4330
    DOI 10.1038/nchem.1689
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  3. Article ; Online: The rise and rise of protein degradation: Opportunities and challenges ahead.

    Hughes, Scott J / Testa, Andrea / Thompson, Nicola / Churcher, Ian

    Drug discovery today

    2021  Volume 26, Issue 12, Page(s) 2889–2897

    Abstract: The transformational mechanism of action underpinning targeted protein degradation strategies, including proteolysis-targeting chimeras (PROTACs), gives potential for potent in vivo pharmacology and has allowed projects to move rapidly to the clinic. ... ...

    Abstract The transformational mechanism of action underpinning targeted protein degradation strategies, including proteolysis-targeting chimeras (PROTACs), gives potential for potent in vivo pharmacology and has allowed projects to move rapidly to the clinic. Despite this remarkable progress, there remain many opportunities to improve current, first-generation approaches even further. Our expanding knowledge will allow discovery of new degrading mechanisms with potential to address several limitations of current approaches, including improving scope and efficiency of degradation, improving drug-like properties of degraders, and reducing potential for the emergence of acquired resistance. Here, we discuss potential routes to realize these advances to expand TPD utility even further.
    MeSH term(s) Drug Design ; Drug Development/methods ; Drug Discovery/methods ; Drug Resistance ; Humans ; Proteins/metabolism ; Proteolysis
    Chemical Substances Proteins
    Language English
    Publishing date 2021-08-20
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/j.drudis.2021.08.006
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  4. Article: Tau therapeutic strategies for the treatment of Alzheimer's disease.

    Churcher, Ian

    Current topics in medicinal chemistry

    2006  Volume 6, Issue 6, Page(s) 579–595

    Abstract: The two classical pathological hallmarks of Alzheimer's disease are deposits of aggregated beta-amyloid (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Abeta pathology, an invariant trait of ... ...

    Abstract The two classical pathological hallmarks of Alzheimer's disease are deposits of aggregated beta-amyloid (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Abeta pathology, an invariant trait of Alzheimer's disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and self-aggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimer's disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH(2)-terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA/cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimer's disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.
    MeSH term(s) Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Animals ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Mitogen-Activated Protein Kinases/metabolism ; Models, Animal ; Nerve Tissue Proteins/metabolism ; Neurofibrillary Tangles/metabolism ; Phosphoric Monoester Hydrolases/metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/metabolism ; tau Proteins/antagonists & inhibitors ; tau Proteins/metabolism
    Chemical Substances Nerve Tissue Proteins ; neuronal Cdk5 activator (p25-p35) ; tau Proteins ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2)
    Language English
    Publishing date 2006-05-19
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ZDB-ID 2064823-6
    ISSN 1873-4294 ; 1568-0266
    ISSN (online) 1873-4294
    ISSN 1568-0266
    DOI 10.2174/156802606776743057
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  5. Article ; Online: Lead-oriented synthesis: a new opportunity for synthetic chemistry.

    Nadin, Alan / Hattotuwagama, Channa / Churcher, Ian

    Angewandte Chemie (International ed. in English)

    2012  Volume 51, Issue 5, Page(s) 1114–1122

    Abstract: The pharmaceutical industry remains solely reliant on synthetic chemistry methodology to prepare compounds for small-molecule drug discovery programmes. The importance of the physicochemical properties of these molecules in determining their success in ... ...

    Abstract The pharmaceutical industry remains solely reliant on synthetic chemistry methodology to prepare compounds for small-molecule drug discovery programmes. The importance of the physicochemical properties of these molecules in determining their success in drug development is now well understood but we present here data suggesting that much synthetic methodology is unintentionally predisposed to producing molecules with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger numbers of compounds from array techniques are prepared. To address this issue we describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of molecules used to develop new medicines.
    MeSH term(s) Chemistry, Pharmaceutical/methods ; Combinatorial Chemistry Techniques ; Drug Design ; Drug Evaluation, Preclinical/methods ; Humans ; Molecular Structure ; Pharmaceutical Preparations/chemistry
    Chemical Substances Pharmaceutical Preparations
    Language English
    Publishing date 2012-01-27
    Publishing country Germany
    Document type Journal Article ; Review
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.201105840
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  6. Article ; Online: Asymmetric synthesis of trisubstituted aziridines via aza-Darzens reaction of chiral sulfinimines.

    Moragas, Toni / Churcher, Ian / Lewis, William / Stockman, Robert A

    Organic letters

    2014  Volume 16, Issue 24, Page(s) 6290–6293

    Abstract: The aza-Darzens reaction of substituted 2-bromoesters with chiral tert-butane- and mesitylsulfinimines provides a rapid access to a range of highly substituted aziridines in good yields and excellent levels of stereoselectivity. The synthetic potential ... ...

    Abstract The aza-Darzens reaction of substituted 2-bromoesters with chiral tert-butane- and mesitylsulfinimines provides a rapid access to a range of highly substituted aziridines in good yields and excellent levels of stereoselectivity. The synthetic potential of this protocol is further enhanced by the successful removal of the sulfinyl motif, yielding simple access to chiral N-H aziridines in just three steps from commercial aldehyde precursors.
    Language English
    Publishing date 2014-12-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1523-7052
    ISSN (online) 1523-7052
    DOI 10.1021/ol502967x
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  7. Article ; Online: Organic synthesis provides opportunities to transform drug discovery.

    Blakemore, David C / Castro, Luis / Churcher, Ian / Rees, David C / Thomas, Andrew W / Wilson, David M / Wood, Anthony

    Nature chemistry

    2018  Volume 10, Issue 4, Page(s) 383–394

    Abstract: Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical ... ...

    Abstract Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.
    MeSH term(s) Chemistry Techniques, Synthetic ; Drug Discovery ; Pharmaceutical Preparations/chemical synthesis ; Pharmaceutical Preparations/chemistry
    Chemical Substances Pharmaceutical Preparations
    Language English
    Publishing date 2018-03-22
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2464596-5
    ISSN 1755-4349 ; 1755-4330
    ISSN (online) 1755-4349
    ISSN 1755-4330
    DOI 10.1038/s41557-018-0021-z
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  8. Article: A systematic approach to diverse, lead-like scaffolds from α,α-disubstituted amino acids

    Foley, Daniel J / Churcher, Ian / Doveston, Richard G / Marsden, Stephen P / Nelson, Adam

    Chemical communications. 2015 June 30, v. 51, no. 56

    2015  

    Abstract: A powerful strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from just four α-amino acid-derived building blocks and a toolkit of six connective reactions. Importantly, ... ...

    Abstract A powerful strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from just four α-amino acid-derived building blocks and a toolkit of six connective reactions. Importantly, each individual scaffold has the ability to specifically target lead-like chemical space.
    Keywords amino acids ; chemical compounds ; chemical reactions
    Language English
    Dates of publication 2015-0630
    Size p. 11174-11177.
    Publishing place The Royal Society of Chemistry
    Document type Article
    ZDB-ID 1472881-3
    ISSN 1364-548X ; 1359-7345 ; 0009-241X
    ISSN (online) 1364-548X
    ISSN 1359-7345 ; 0009-241X
    DOI 10.1039/c5cc03002a
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  9. Article ; Online: Optimization of a Series of RIPK2 PROTACs.

    Miah, Afjal H / Smith, Ian E D / Rackham, Mark / Mares, Alina / Thawani, Aditya R / Nagilla, Rakesh / Haile, Pamela A / Votta, Bartholomew J / Gordon, Laurie J / Watt, Gillian / Denyer, Jane / Fisher, Don T / Dace, Phoebe / Giffen, Paul / Goncalves, Andrea / Churcher, Ian / Scott-Stevens, Paul / Harling, John D

    Journal of medicinal chemistry

    2021  Volume 64, Issue 17, Page(s) 12978–13003

    Abstract: Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ... ...

    Abstract Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound
    MeSH term(s) Animals ; Drug Design ; Gene Expression Regulation/drug effects ; Half-Life ; Humans ; Male ; Molecular Structure ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics ; Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism ; THP-1 Cells
    Chemical Substances RIPK2 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinase 2 (EC 2.7.11.1)
    Language English
    Publishing date 2021-08-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.1c01118
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  10. Article ; Online: A systematic approach to diverse, lead-like scaffolds from α,α-disubstituted amino acids.

    Foley, Daniel J / Doveston, Richard G / Churcher, Ian / Nelson, Adam / Marsden, Stephen P

    Chemical communications (Cambridge, England)

    2015  Volume 51, Issue 56, Page(s) 11174–11177

    Abstract: A powerful strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from just four α-amino acid-derived building blocks and a toolkit of six connective reactions. Importantly, ... ...

    Abstract A powerful strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from just four α-amino acid-derived building blocks and a toolkit of six connective reactions. Importantly, each individual scaffold has the ability to specifically target lead-like chemical space.
    MeSH term(s) Amino Acids/chemistry ; Azabicyclo Compounds/chemical synthesis ; Azabicyclo Compounds/chemistry ; Azepines/chemical synthesis ; Azepines/chemistry ; Molecular Structure ; Pyridines/chemical synthesis ; Pyridines/chemistry
    Chemical Substances Amino Acids ; Azabicyclo Compounds ; Azepines ; Pyridines
    Language English
    Publishing date 2015-06-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1472881-3
    ISSN 1364-548X ; 1359-7345 ; 0009-241X
    ISSN (online) 1364-548X
    ISSN 1359-7345 ; 0009-241X
    DOI 10.1039/c5cc03002a
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