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Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength)	Build–couple–transform: a paradigm for lead-like library synthesis with scaffold diversity Mélanie Uguen , Gemma Davison , Lukas J. Sprenger , James H. Hunter , Mathew P. Martin , Shannon Turberville , Jessica Watt , Bernard T. Golding , Martin E. N. Noble , Hannah L. Stewart , Michael J. Waring Journal Of Medicinal Chemistry 65, 11322 - 11339 DOI: 10.1021/acs.jmedchem.2c00897 Open Access Show Abstract ▼ Abstract: High-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks using single reaction types. We address this problem through a “build–couple–transform” paradigm for the generation of lead-like libraries with scaffold diversity. Nineteen transformations of a 4-oxo-2-butenamide scaffold template were optimized, including 1,4-cyclizations, 3,4-cyclizations, reductions, and 1,4-additions. A pool-transformation approach efficiently explored the scope of these transformations for nine different building blocks and synthesized a >170-member library with enhanced chemical space coverage and favorable drug-like properties. Screening revealed hits against CDK2. This work establishes the build–couple–transform concept for the synthesis of lead-like libraries and provides a differentiated approach to libraries with significantly enhanced scaffold diversity.	Aug 2022
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Parallel optimization of potency and pharmacokinetics leading to the discovery of a pyrrole carboxamide ERK5 kinase domain inhibitor Duncan C. Miller , Tristan Reuillon , Lauren Molyneux , Timothy Blackburn , Simon J. Cook , Noel Edwards , Jane A. Endicott , Bernard T. Golding , Roger J. Griffin , Ian Hardcastle , Suzannah J. Harnor , Amy Heptinstall , Pamela Lochhead , Mathew P. Martin , Nick C. Martin , Stephanie Myers , David R. Newell , Richard A. Noble , Nicole Phillips , Laurent Rigoreau , Huw Thomas , Julie A. Tucker , Lan-Zhen Wang , Michael J. Waring , Ai-Ching Wong , Stephen R. Wedge , Martin E. M. Noble , Celine Cano Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01756 Diamond Proposal Number(s): [9948, 13587] Show Abstract ▼ Abstract: The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.	Apr 2022
I04-Macromolecular Crystallography	Structure-based design of potent and orally active isoindolinone inhibitors of MDM2-p53 protein–protein interaction Gianni Chessari , Ian R. Hardcastle , Jong Sook Ahn , Burcu Anil , Elizabeth Anscombe , Ruth H. Bawn , Luke D. Bevan , Timothy J. Blackburn , Ildiko Buck , Celine Cano , Benoit Carbain , Juan Castro , Ben Cons , Sarah J. Cully , Jane A. Endicott , Lynsey Fazal , Bernard T. Golding , Roger J. Griffin , Karen Haggerty , Suzannah J. Harnor , Keisha Hearn , Stephen Hobson , Rhian S. Holvey , Steven Howard , Claire E. Jennings , Christopher N. Johnson , John Lunec , Duncan C. Miller , David R. Newell , Martin E. M. Noble , Judith Reeks , Charlotte H. Revill , Christiane Riedinger , Jeffrey D. St. Denis , Emiliano Tamanini , Huw Thomas , Neil T. Thompson , Mladen Vinković , Stephen R. Wedge , Pamela A. Williams , Nicola E. Wilsher , Bian Zhang , Yan Zhao Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c02188 Show Abstract ▼ Abstract: Inhibition of murine double minute 2 (MDM2)-p53 protein–protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.	Mar 2021
I04-Macromolecular Crystallography	2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase Christopher J. Matheson , Christopher R. Coxon , Richard Bayliss , Kathy Boxall , Benoit Carbain , Andrew M. Fry , Ian R. Hardcastle , Suzannah J. Harnor , Corine Mas-Droux , David R. Newell , Mark W. Richards , Mangaleswaran Sivaprakasam , David Turner , Roger J. Griffin , Bernard T. Golding , Céline Cano Rsc Medicinal Chemistry 49 DOI: 10.1039/D0MD00074D Open Access Show Abstract ▼ Abstract: Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5–10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2.	May 2020
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4 Stephanie Myers , Duncan C. Miller , Lauren Molyneux , Mercedes Arasta , Ruth H. Bawn , Timothy Blackburn , Simon J. Cook , Noel Edwards , Jane A. Endicott , Bernard T. Golding , Roger J. Griffin , Tim Hammonds , Ian R. Hardcastle , Suzannah J. Harnor , Amy Heptinstall , Pamela Lochhead , Mathew P. Martin , Nick C. Martin , David R. Newell , Paul J. Owen , Leon C. Pang , Tristan Reuillon , Laurent J. M. Rigoreau , Huw Thomas , Julie A. Tucker , Lan-Zhen Wang , Ai-Ching Wong , Martin E. M. Noble , Stephen R. Wedge , Celine Cano European Journal Of Medicinal Chemistry DOI: 10.1016/j.ejmech.2019.05.057 Diamond Proposal Number(s): [9948, 13587] Show Abstract ▼ Abstract: Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4-position with an aroyl group being found to exhibit IC50 values in the micromolar range, but having no selectivity against p38α MAP kinase. Truncation of the N-substituent marginally enhanced potency (∼3-fold) against ERK5, but importantly attenuated inhibition of p38α. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 μM for ERK5; IC50 > 120 μM for p38α). The crystal structure (PDB 5O7I) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases.	May 2019
	Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach Duncan C. Miller , Mathew P. Martin , Santosh Adhikari , Alfie Brennan , Jane A. Endicott , Bernard T. Golding , Ian R. Hardcastle , Amy Heptinstall , Stephen Hobson , Claire Jennings , Lauren Molyneux , Yvonne Ng , Stephen R. Wedge , Martin Noble , Celine Cano Organic & Biomolecular Chemistry 21 DOI: 10.1039/C8OB00099A Open Access Show Abstract ▼ Abstract: ATAD2 is an ATPase that is overexpressed in a variety of cancers and associated with a poor patient prognosis. This protein has been suggested to function as a cofactor for a range of transcription factors, including the proto-oncogene MYC and the androgen receptor. ATAD2 comprises an ATPase domain, implicated in chromatin remodelling, and a bromodomain which allows it to interact with acetylated histone tails. Dissection of the functional roles of these two domains would benefit from the availability of selective, cell-permeable pharmacological probes. An in silico evaluation of the 3D structures of various bromodomains suggested that developing small molecule ligands for the bromodomain of ATAD2 is likely to be challenging, although recent reports have shown that ATAD2 bromodomain ligands can be identified. We report a structure-guided fragment-based approach to identify lead compounds for ATAD2 bromodomain inhibitor development. Our findings indicate that the ATAD2 bromodomain can accommodate fragment hits (Mr < 200) that yield productive structure–activity relationships, and structure-guided design enabled the introduction of selectivity over BRD4.	Feb 2018
I04-1-Macromolecular Crystallography (fixed wavelength)	Cyclin-dependent kinase (CDK) inhibitors: structure–activity relationships and insights into the CDK-2 selectivity of 6-substituted 2-arylaminopurines Christopher R Coxon , Elizabeth Anscombe , Suzannah Jane Harnor , Mathew P. Martin , Benoit Jean-Pierre Carbain , Bernard Thomas Golding , Ian Robert Hardcastle , Lisa K Harlow , Svitlana Korolchuk , Christopher J. Matheson , David R. Newell , Martin E. M. Noble , Mangaleswaran Sivaprakasam , Susan J. Tudhope , David M. Turner , Lan-Zhen Wang , Stephen R Wedge , Christopher Wong , Roger John Griffin , Jane A. Endicott , Celine Cano Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.6b01254 Diamond Proposal Number(s): [13587] Open Access Show Abstract ▼ Abstract: Purines and related heterocycles substituted at C-2 with 4’-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favour competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1'-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency towards CDK2 (IC50 0.044 μM), but was ~ 2000-fold less active towards CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket, and that is preferred in CDK2, but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.	Dec 2016
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-guided design of purine-based probes for selective Nek2 inhibition Christopher R. Coxon , Christopher Wong , Richard Bayliss , Kathy Boxall , Katherine H. Carr , Andrew M. Fry , Ian R. Hardcastle , Christopher J. Matheson , David R. Newell , Mangaleswaran Sivaprakasam , Huw Thomas , David Turner , Sharon Yeoh , Lan Z. Wang , Roger J. Griffin , Bernard T. Golding , Céline Cano Oncotarget DOI: 10.18632/oncotarget.13249 Diamond Proposal Number(s): [307, 6385] Open Access Show Abstract ▼ Abstract: Nek2 (NIMA-related kinase 2) is a cell cycle-dependent serine/threonine protein kinase that regulates centrosome separation at the onset of mitosis. Overexpression of Nek2 is common in human cancers and suppression can restrict tumor cell growth and promote apoptosis. Nek2 inhibition with small molecules, therefore, offers the prospect of a new therapy for cancer. To achieve this goal, a better understanding of the requirements for selective-inhibition of Nek2 is required. 6-Alkoxypurines were identified as ATP-competitive inhibitors of Nek2 and CDK2. Comparison with CDK2-inhibitor structures indicated that judicious modification of the 6-alkoxy and 2-arylamino substituents could achieve discrimination between Nek2 and CDK2. In this study, a library of 6-cyclohexylmethoxy-2-arylaminopurines bearing carboxamide, sulfonamide and urea substituents on the 2-arylamino ring was synthesized. Few of these compounds were selective for Nek2 over CDK2, with the best result being obtained for 3-((6-(cyclohexylmethoxy)-9H-purin-2-yl)amino)-N,N-dimethylbenzamide (CDK2 IC50 = 7.0 μM; Nek2 IC50 = 0.62 μM) with >10-fold selectivity. Deletion of the 6-substituent abrogated activity against both Nek2 and CDK2. Nine compounds containing an (E)-dialkylaminovinyl substituent at C-6, all showed selectivity for Nek2, e.g. (E)-6-(2-(azepan-1-yl)vinyl)-N-phenyl-9H-purin-2-amine (CDK2 IC50 = 2.70 μM; Nek2 IC50 = 0.27 μM). Structural biology of selected compounds enabled a partial rationalization of the observed structure activity relationships and mechanism of Nek2 activation. This showed that carboxamide 11 is the first reported inhibitor of Nek2 in the DFG-in conformation.	Nov 2016
I04-1-Macromolecular Crystallography (fixed wavelength)	Identification and characterization of an irreversible inhibitor of CDK2 Elizabeth Anscombe , Elisa Meschini , Regina Mora-Vidal , Mathew p. Martin , David Staunton , Matthis Geitmann , U. helena Danielson , Will a. Stanley , Lan z. Wang , Tristan Reuillon , Bernard t. Golding , Celine Cano , David r. Newell , Martin Noble , Stephen r. Wedge , Jane a. Endicott , Roger j. Griffin Chemistry & Biology 22 (9), 1159 - 1164 DOI: 10.1016/j.chembiol.2015.07.018 PMID: 26320860 Open Access Show Abstract ▼ Abstract: Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)-9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.	Sep 2015
I04-1-Macromolecular Crystallography (fixed wavelength)	8-substituted O6-cyclohexylmethylguanine CDK2 inhibitors: using structure-based inhibitor design to optimize an alternative binding mode Benoit Carbain , David J. Paterson , Elizabeth Anscombe , Allyson J. Campbell , Celine Cano , Aude Echalier , Jane A. Endicott , Bernard T. Golding , Karen Haggerty , Ian R. Hardcastle , Philip J. Jewsbury , David R. Newell , Martin E. M. Noble , Celine Roche , Lan Z. Wang , Roger J. Griffin Journal Of Medicinal Chemistry 57 (1), 56 - 70 DOI: 10.1021/jm401555v PMID: 24304238 Show Abstract ▼ Abstract: Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O6-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a “reverse” binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these “reverse” binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.	Dec 2013

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