Publications by authors named "Matthew W D Perry"

21 Publications

  • Page 1 of 1

PI3K inhibitors are finally coming of age.

Nat Rev Drug Discov 2021 Jun 14. Epub 2021 Jun 14.

Department of Pathology, University of Cambridge, Cambridge, UK.

Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval - the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities.
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http://dx.doi.org/10.1038/s41573-021-00209-1DOI Listing
June 2021

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

J Med Chem 2021 Jun 3;64(12):8053-8075. Epub 2021 Jun 3.

Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00434DOI Listing
June 2021

Glucocorticoid receptor Thr524 phosphorylation by MINK1 induces interactions with 14-3-3 protein regulators.

J Biol Chem 2021 Jan-Jun;296:100551. Epub 2021 Mar 17.

Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. Electronic address:

The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that plays a central role in inflammation. The GR activity is also modulated via protein-protein interactions, including binding of 14-3-3 proteins induced by GR phosphorylation. However, the specific phosphorylation sites on the GR that trigger these interactions and their functional consequences are less clear. Hence, we sought to examine this system in more detail. We used phosphorylated GR peptides, biophysical studies, and X-ray crystallography to identify key residues within the ligand-binding domain of the GR, T524 and S617, whose phosphorylation results in binding of the representative 14-3-3 protein 14-3-3ζ. A kinase screen identified misshapen-like kinase 1 (MINK1) as responsible for phosphorylating T524 and Rho-associated protein kinase 1 for phosphorylating S617; cell-based approaches confirmed the importance of both GR phosphosites and MINK1 but not Rho-associated protein kinase 1 alone in inducing GR-14-3-3 binding. Together our results provide molecular-level insight into 14-3-3-mediated regulation of the GR and highlight both MINK1 and the GR-14-3-3 axis as potential targets for future therapeutic intervention.
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http://dx.doi.org/10.1016/j.jbc.2021.100551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080530PMC
March 2021

14-3-3 modulation of the inflammatory response.

Pharmacol Res 2021 01 11;163:105236. Epub 2020 Oct 11.

Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. Electronic address:

Regulation of inflammation is a central part of the maintenance of homeostasis by the immune system. One important class of regulatory protein that has been shown to have effects on the inflammatory process are the 14-3-3 proteins. Herein we describe the roles that have been identified for 14-3-3 in regulation of the inflammatory response. These roles encompass regulation of the response that affect inflammation at the genetic, molecular and cellular levels. At a genetic level 14-3-3 is involved in the regulation of multiple transcription factors and affects the transcription of key effectors of the immune response. At a molecular level many of the constituent parts of the inflammatory process, such as pattern recognition receptors, protease activated receptors and cytokines are regulated through phosphorylation and recognition by 14-3-3 whilst disruption of the recognition processes has been observed to result in clinical syndromes. 14-3-3 is also involved in the regulation of cell proliferation and differentiation, this has been shown to affect the immune system, particularly T- and B-cells. Finally, we discuss how abnormal levels of 14-3-3 contribute to undesirable immune responses and chronic inflammatory conditions.
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http://dx.doi.org/10.1016/j.phrs.2020.105236DOI Listing
January 2021

Identification of Phosphate-Containing Compounds as New Inhibitors of 14-3-3/c-Abl Protein-Protein Interaction.

ACS Chem Biol 2020 04 20;15(4):1026-1035. Epub 2020 Mar 20.

Department of Biotechnology, Chemistry and Pharmacy-Department of Excellence 2018-2022, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy.

The 14-3-3/c-Abl protein-protein interaction (PPI) is related to carcinogenesis and in particular to pathogenesis of chronic myeloid leukemia (CML). Previous studies have demonstrated that molecules able to disrupt this interaction improve the nuclear translocation of c-Abl, inducing apoptosis in leukemia cells. Through an X-ray crystallography screening program, we have identified two phosphate-containing compounds, inosine monophosphate (IMP) and pyridoxal phosphate (PLP), as binders of human 14-3-3σ, by targeting the protein amphipathic groove. Interestingly, they also act as weak inhibitors of the 14-3-3/c-Abl PPI, demonstrated by NMR, SPR, and FP data. A 37-compound library of PLP and IMP analogues was investigated using a FP assay, leading to the identification of three further molecules acting as weak inhibitors of the 14-3-3/c-Abl complex formation. The antiproliferative activity of IMP, PLP, and the three derivatives was tested against K-562 cells, showing that the parent compounds had the most pronounced effect on tumor cells. PLP and IMP were also effective in promoting the c-Abl nuclear translocation in c-Abl overexpressing cells. Further, these compounds demonstrated low cytotoxicity on human Hs27 fibroblasts. In conclusion, our data suggest that 14-3-3σ targeting compounds represent promising hits for further development of drugs against c-Abl-dependent cancers.
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http://dx.doi.org/10.1021/acschembio.0c00039DOI Listing
April 2020

Design, Synthesis, and Biological Evaluation of MEK PROTACs.

J Med Chem 2020 01 20;63(1):157-162. Epub 2019 Dec 20.

Pharmaron Beijing Company, Limited , No. 6 Taihe Road, BDA , Beijing 100176 , P.R. China.

PROteolysis TArgeting Chimeras (PROTACs) targeting the degradation of MEK have been designed based on allosteric MEK inhibitors. Inhibition of the phosphorylation of ERK1/2 was less effective with the PROTACs than a small-molecule inhibitor; the best PROTACs, however, were more effective in inhibiting proliferation of A375 cells than an inhibitor.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00810DOI Listing
January 2020

A class of highly selective inhibitors bind to an active state of PI3Kγ.

Nat Chem Biol 2019 04 4;15(4):348-357. Epub 2019 Feb 4.

Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

We have discovered a class of PI3Kγ inhibitors exhibiting over 1,000-fold selectivity over PI3Kα and PI3Kβ. On the basis of X-ray crystallography, hydrogen-deuterium exchange-mass spectrometry and surface plasmon resonance experiments we propose that the cyclopropylethyl moiety displaces the DFG motif of the enzyme away from the adenosine tri-phosphate binding site, inducing a large conformational change in both the kinase- and helical domains of PI3Kγ. Site directed mutagenesis explained how the conformational changes occur. Our results suggest that these cyclopropylethyl substituted compounds selectively inhibit the active state of PI3Kγ, which is unique to these compounds and to the PI3Kγ isoform, explaining their excellent potency and unmatched isoform selectivity that were confirmed in cellular systems. This is the first example of a Class I PI3K inhibitor achieving its selectivity by affecting the DFG motif in a manner that bears similarity to DFG in/out for type II protein kinase inhibitors.
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http://dx.doi.org/10.1038/s41589-018-0215-0DOI Listing
April 2019

Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases.

J Med Chem 2019 05 24;62(10):4783-4814. Epub 2018 Dec 24.

Respiratory, Inflammation & Autoimmunity Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit , AstraZeneca , Boston , Massachusetts 02451 , United States.

Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01298DOI Listing
May 2019

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors.

J Med Chem 2018 06 18;61(12):5435-5441. Epub 2018 Jun 18.

Pharmaron Beijing Co., Ltd. , No. 6 Taihe Road, BDA , Beijing 100176 , P. R. China.

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00447DOI Listing
June 2018

Stabilization of protein-protein interactions in drug discovery.

Expert Opin Drug Discov 2017 09 11;12(9):925-940. Epub 2017 Jul 11.

a Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems , Eindhoven University of Technology , Eindhoven , The Netherlands.

Introduction: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.
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http://dx.doi.org/10.1080/17460441.2017.1346608DOI Listing
September 2017

Design and Synthesis of Soluble and Cell-Permeable PI3Kδ Inhibitors for Long-Acting Inhaled Administration.

J Med Chem 2017 06 7;60(12):5057-5071. Epub 2017 Jun 7.

Pharmaron Beijing Co., Ltd. , No. 6 Taihe Road, BDA, Beijing 100176, P.R. China.

PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesized to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work, we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimization for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC > 9), and by careful manipulation of the pK and lipophilicity, we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in vivo studies where significant target engagement could be demonstrated.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00401DOI Listing
June 2017

Structural and conformational determinants of macrocycle cell permeability.

Nat Chem Biol 2016 12 17;12(12):1065-1074. Epub 2016 Oct 17.

Department of Chemistry, Uppsala University, Uppsala, Sweden.

Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.
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http://dx.doi.org/10.1038/nchembio.2203DOI Listing
December 2016

Designing novel building blocks is an overlooked strategy to improve compound quality.

Drug Discov Today 2015 Jan 2;20(1):11-7. Epub 2014 Oct 2.

AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.

One pragmatic way to improve compound quality, while enhancing and accelerating drug discovery projects, is the ability to access a high quality, novel, diverse building block collection. Here, we outline general principles that should be applied to ensure that a building block collection has the greatest impact on drug discovery projects, by discussing design principles for novel reagents and what types of reagents are popular with medicinal chemists in general. We initiated a program in 2009 to address this, which has already delivered three candidate drugs, and the success of that program provides evidence that focussing on building block design is a useful strategy for drug discovery.
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http://dx.doi.org/10.1016/j.drudis.2014.09.023DOI Listing
January 2015

Impact of stereospecific intramolecular hydrogen bonding on cell permeability and physicochemical properties.

J Med Chem 2014 Mar 26;57(6):2746-54. Epub 2014 Feb 26.

CVMD iMed, AstraZeneca R&D Mölndal , SE-431 83 Mölndal, Sweden.

Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pKa, and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH→NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure-property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski's rule of 5.
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http://dx.doi.org/10.1021/jm500059tDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968888PMC
March 2014

The discovery of CCR3/H1 dual antagonists with reduced hERG risk.

Bioorg Med Chem Lett 2012 Nov 15;22(21):6688-93. Epub 2012 Sep 15.

Department of Bioscience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, United Kingdom.

A series of dual CCR3/H(1) antagonists based on a bispiperidine scaffold were discovered. Introduction of an acidic group overcame hERG liability. Bioavailability was optimised by modulation of physico-chemical properties and physical form to deliver a compound suitable for clinical evaluation.
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http://dx.doi.org/10.1016/j.bmcl.2012.08.124DOI Listing
November 2012

Scaffold-hopping with zwitterionic CCR3 antagonists: identification and optimisation of a series with good potency and pharmacokinetics leading to the discovery of AZ12436092.

Bioorg Med Chem Lett 2012 Nov 11;22(21):6694-9. Epub 2012 Sep 11.

Department of Bioscience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, United Kingdom.

The discovery and optimisation of a series of zwitterionic CCR3 antagonists is described. Optimisation of the structure led to AZ12436092, a compound with excellent selectivity over activity at hERG and outstanding pharmacokinetics in preclinical species.
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http://dx.doi.org/10.1016/j.bmcl.2012.08.103DOI Listing
November 2012

Spiro-fused pyrrolidine, piperidine, and oxindole scaffolds from lactams.

Org Lett 2012 Sep 4;14(18):4846-9. Epub 2012 Sep 4.

School of Chemistry, University of Bristol , Bristol, BS8 1TS, UK.

Expedient routes to three classes of novel spiro-fused pyrrolidine, piperidine, and indoline heterocycle scaffolds are described. These three-dimensional frameworks, which conform to the "rule of three", are suitably protected to allow for site-selective manipulation and functionalization. Different modes of substrate control were explored, which allow for good to excellent levels of diastereoselectivity and dispense with the need for additional chiral reagents or catalysts. The concepts developed were applied in short, formal syntheses of (±)-coerulescine and (±)-horsfiline.
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http://dx.doi.org/10.1021/ol302176zDOI Listing
September 2012

A practical method for targeted library design balancing lead-like properties with diversity.

ChemMedChem 2009 May;4(5):800-8

Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics, LE11 5RH, UK.

A practical and pragmatic method is demonstrated that aligns lead-like properties with compound diversity for the picking of compounds to synthesise from large virtual libraries. Methods are highlighted for decreasing synthetic attrition through the prior filtration of reagents sets grouped by reaction type. Also disclosed are protocols that use a combination of predicted physicochemical parameters and potential toxicological liabilities to enable the synthesis of lead-like compounds with a low potential risk of exhibiting toxicity or undesirable physicochemical properties. Lastly, a compound-picking process for a 2D compound matrix is demonstrated that maximises the diversity coverage whilst minimising synthetic effort. Thus a very highly optimised process is shown that delivers premium sample quality where lead-likeness and novelty are aligned to afford the best possible enhancement for the corporate compound collection.
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http://dx.doi.org/10.1002/cmdc.200900050DOI Listing
May 2009

Monocarboxylate transporter MCT1 is a target for immunosuppression.

Nat Chem Biol 2005 Dec;1(7):371-6

Department of Discovery BioScience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK.

Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.
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http://dx.doi.org/10.1038/nchembio744DOI Listing
December 2005

[3 + 2] cycloaddition reactions of 4-alkyl-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium inner salts.

J Org Chem 2003 Oct;68(22):8700-3

Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, United Kingdom.

Heating dipolarophiles with 4-alkyl-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide inner salts results in [3 + 2] cycloaddition across positions 3a and 5 of the aromatic system to give the [3 + 2] cycloadducts in good yield. When the 4-alkyl substituent is a 2-acetate ester and the methylene group can be deprotonated, a second mode of [3 + 2] cycloaddition becomes available for the resulting anion (across the side chain methine group and position 5 of the aromatic system) and occurs under basic conditions, allowing either of two modes of [3 + 2] cycloaddition to be selected by appropriate choice of reaction conditions.
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http://dx.doi.org/10.1021/jo034160fDOI Listing
October 2003