I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Gavin W.
Collie
,
Louise
Barlind
,
Sana
Bazzaz
,
Ulf
Börjesson
,
Ian L.
Dale
,
Jeremy S.
Disch
,
Sevan
Habeshian
,
Rachael
Jetson
,
Puneet
Khurana
,
Andrew
Madin
,
Iacovos N.
Michaelides
,
Ling
Peng
,
Arjan
Snijder
,
Christopher J.
Stubbs
Diamond Proposal Number(s):
[17180, 20015]
Open Access
Abstract: The c-MET receptor tyrosine kinase has received considerable attention as a cancer drug target yet there remains a need for inhibitors which are selective for c-MET and able to target emerging drug-resistant mutants. We report here the discovery, by screening a DNA-encoded chemical library, of a highly selective c-MET inhibitor which was shown by X-ray crystallography to bind to the kinase in an unprecedented manner. These results represent a novel mode of inhibiting c-MET with a small molecule and may provide a route to targeting drug-resistant forms of the kinase whilst avoiding potential toxicity issues associated with broad kinome inhibition.
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Aug 2022
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I03-Macromolecular Crystallography
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Francesca
Quartieri
,
Marcella
Nesi
,
Nilla R.
Avanzi
,
Daniela
Borghi
,
Elena
Casale
,
Emiliana
Corti
,
Ulisse
Cucchi
,
Daniele
Donati
,
Marina
Fasolini
,
Eduard R.
Felder
,
Arturo
Galvani
,
Maria L.
Giorgini
,
Antonio
Lomolino
,
Maria
Menichincheri
,
Christian
Orrenius
,
Claudia
Perrera
,
Stefania
Re Depaolini
,
Federico
Riccardi-Sirtori
,
Enea
Salsi
,
Antonella
Isacchi
,
Paola
Gnocchi
Diamond Proposal Number(s):
[26586]
Abstract: In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.
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Nov 2021
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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John
Liddle
,
Andrew C.
Pearce
,
Christopher
Arico-Muendel
,
Svetlana
Belyanskaya
,
Andrew
Brewster
,
Murray
Brown
,
Chun-Wa
Chung
,
Alexis
Denis
,
Nerina
Dodic
,
Anthony
Dossang
,
Peter
Eddershaw
,
Diana
Klimaszewska
,
Imran
Haq
,
Duncan S.
Holmes
,
Alistair
Jagger
,
Toral
Jakhria
,
Emilie
Jigorel
,
Ken
Lind
,
Jeff
Messer
,
Margaret
Neu
,
Allison
Olszewski
,
Riccardo
Ronzoni
,
James
Rowedder
,
Martin
Rüdiger
,
Steve
Skinner
,
Kathrine J.
Smith
,
Lionel
Trottet
,
Iain
Uings
,
Zhengrong
Zhu
,
James A.
Irving
,
David A.
Lomas
Diamond Proposal Number(s):
[23853, 17201]
Abstract: α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.
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Jun 2021
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Daniel H.
O' Donovan
,
Clare
Gregson
,
Martin J.
Packer
,
Ryan
Greenwood
,
Kurt G.
Pike
,
Sameer
Kawatkar
,
Andrew
Bloecher
,
James
Robinson
,
Jon
Read
,
Erin
Code
,
Jessie Hao-Ru
Hsu
,
Minhui
Shen
,
Haley
Woods
,
Peter
Barton
,
Shaun
Fillery
,
Beth
Williamson
,
Philip B.
Rawlins
,
Sharan K.
Bagal
Abstract: Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.
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May 2021
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I02-Macromolecular Crystallography
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Diamond Proposal Number(s):
[14043]
Abstract: Inosine-5′-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme involved in nucleotide biosynthesis. Because of its critical role in purine biosynthesis, IMPDH is a drug design target for immunosuppressive, anticancer, antiviral and antimicrobial chemotherapy. In this study, we use mass spectrometry and X-ray crystallography to show that the inhibitor 6-Cl-purine ribotide forms a covalent adduct with the Cys-341 residue of Mycobacterium thermoresistibile IMPDH.
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Jan 2020
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I04-Macromolecular Crystallography
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Ann L.
Walker
,
Alexis
Denis
,
Ryan P.
Bingham
,
Anne
Boulliot
,
Emma V.
Edgar
,
Alan
Ferrie
,
Duncan S.
Holmes
,
Alain
Laroze
,
John
Liddle
,
Marie-Helene
Fouchet
,
Alexandre
Moquette
,
Pam
Nassau
,
Andrew C.
Pearce
,
Oxana
Polyakova
,
Kathrine J.
Smith
,
Pamela
Thomas
,
James H.
Thorpe
,
Lionel
Trottet
,
Yichen
Wang
,
Alain
Hovnanian
Diamond Proposal Number(s):
[5799]
Abstract: The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.
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Oct 2019
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I03-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Benjamin N.
Atkinson
,
David
Steadman
,
William
Mahy
,
Yuguang
Zhao
,
James
Sipthorp
,
Elliott D.
Bayle
,
Fredrik
Svensson
,
George
Papageorgiou
,
Fiona
Jeganathan
,
Sarah
Frew
,
Amy
Monaghan
,
Magda
Bictash
,
E.
Yvonne Jones
,
Paul V.
Fish
Diamond Proposal Number(s):
[14744]
Open Access
Abstract: The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.
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Oct 2019
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I02-Macromolecular Crystallography
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Abstract: In silico virtual screening using the ligand-based ROCS approach and the commercially purchasable compound collection from the ZINC database resulted in the identification of distinctly different and novel acetamide core frameworks with series representatives 1a and 2a exhibiting nanomolar affinity in the kinase domain only hTrkA HTRF biochemical assay. Additional experimental validation using the Caliper technology with either the active or inactive kinase conditions demonstrated the leads, 1a and 2a, to preferentially bind the kinase inactive state. X-ray structural analysis of the kinase domain of hTrkA…1a/2a complexes confirmed the kinase, bind the inhibitor leads in the inactive state and to exhibit a type 2 binding mode with the DFG-out and αC-helix out conformation. The leads also demonstrated sub-micromolar activity in the full length hTrkA cell-based assay and selectivity against the closely related hTrkB isoform. However, the poor microsomal stability and permeability of the leads is suggestive of a multiparametric lead optimization effort requirement for further progression.
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Aug 2019
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I03-Macromolecular Crystallography
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Jon
Read
,
Iain T.
Collie
,
Michelle
Nguyen-Mccarty
,
Christopher
Lucaj
,
James
Robinson
,
Leslie
Conway
,
Jayanta
Mukherjee
,
Eileen
Mccall
,
Gerard
Donohoe
,
Elizabeth
Flavell
,
Karolina
Peciak
,
Juli
Warwicker
,
Carly
Dix
,
Bernard G.
Van Den Hoven
,
Andrew
Madin
,
Dean G.
Brown
,
Stephen
Moss
,
Stephen J.
Haggarty
,
Nicholas J.
Brandon
,
Roland W.
Bürli
Abstract: The TRAF2 and NCK interacting kinase (TNIK) has been proposed to play a role in cytoskeletal organization and synaptic plasticity and has been linked, among others, to neurological disorders. However, target validation efforts for TNIK have been hampered by the limited kinase selectivity of small molecule probes and possible functional compensation in mouse models. Both issues are at least in part due to its close homology to the kinases MINK1 (or MAP4K6) and MAP4K4 (or HGK). As part of our interest in validating TNIK as a therapeutic target for neurological diseases, we set up a panel of biochemical and cellular assays, which are described herein. We then examined the activity of known amino-pyridine-based TNIK inhibitors (1, 3) and prepared structurally very close analogs that lack the ability to inhibit the target. We also developed a structurally orthogonal, naphthyridine-based TNIK inhibitor (9) and an inactive control molecule of the same chemical series. These validated small-molecule probes will enable dissection of the function of TNIK family in the context of human disease biology.
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Aug 2019
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I02-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
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Mark
Zak
,
Emily J.
Hanan
,
Patrick
Lupardus
,
David G.
Brown
,
Colin
Robinson
,
Michael
Siu
,
Joseph P.
Lyssikatos
,
F. Anthony
Romero
,
Guiling
Zhao
,
Terry
Kellar
,
Rohan
Mendonca
,
Nicholas C.
Ray
,
Simon C.
Goodacre
,
Peter H.
Crackett
,
Neville
Mclean
,
Christopher A.
Hurley
,
Po-Wai
Yuen
,
Yun-Xing
Cheng
,
Xiongcai
Liu
,
Marya
Liimatta
,
Pawan Bir
Kohli
,
Jim
Nonomiya
,
Gary
Salmon
,
Gerry
Buckley
,
Julia
Lloyd
,
Paul
Gibbons
,
Nico
Ghilardi
,
Jane R.
Kenny
,
Adam
Johnson
Diamond Proposal Number(s):
[5069, 14629]
Abstract: Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50’s in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).
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Apr 2019
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