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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Diverse, potent, and efficacious inhibitors that target the EED subunit of the polycomb repressive complex 2 methyltransferase Sharan K. Bagal , Clare Gregson , Daniel H. O’ Donovan , Kurt G. Pike , Andrew Bloecher , Peter Barton , Alexandra Borodovsky , Erin Code , Shaun M. Fillery , Jessie Hao-Ru Hsu , Sameer P. Kawatkar , Chengzhi Li , David Longmire , Youfeng Nai , Samuel C. Nash , Andrew Pike , James Robinson , Jon A. Read , Phillip B. Rawlins , Minhui Shen , Jia Tang , Peng Wang , Haley Woods , Beth Williamson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01161 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved for the treatment of epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the EED subunit of PRC2 have recently emerged as allosteric inhibitors of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors that target EZH2, small molecules that bind to EED retain their efficacy in EZH2 inhibitor-resistant cell lines. In this paper we disclose the discovery of potent and orally bioavailable EED ligands with good solubilities. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.	Nov 2021
I04-1-Macromolecular Crystallography (fixed wavelength)	Free energy perturbation in the design of EED ligands as inhibitors of polycomb repressive complex 2 (PRC2) methyltransferase 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 Bioorganic & Medicinal Chemistry Letters 39 DOI: 10.1016/j.bmcl.2021.127904 Show Abstract ▼ 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.	May 2021
I03-Macromolecular Crystallography	Discovery of AZD9833, a potent and orally bioavailable selective estrogen receptor degrader and antagonist James S. Scott , Thomas A. Moss , Amber Balazs , Bernard Barlaam , Jason Breed , Rodrigo J. Carbajo , Elisabetta Chiarparin , Paul R. J. Davey , Oona Delpuech , Stephen Fawell , David I. Fisher , Sladjana Gagrica , Eric T. Gangl , Tyler Grebe , Ryan D. Greenwood , Sudhir Hande , Holia Hatoum-Mokdad , Kara Herlihy , Samantha Hughes , Thomas A. Hunt , Hoan Huynh , Sophie L. M. Janbon , Tony Johnson , Stefan Kavanagh , Teresa Klinowska , Mandy Lawson , Andrew S. Lister , Stacey Marden , Dermot F. Mcginnity , Christopher J. Morrow , J. Willem M. Nissink , Daniel H. O’donovan , Bo Peng , Radoslaw Polanski , Darren S. Stead , Stephen Stokes , Kumar Thakur , Scott R. Throner , Michael J. Tucker , Jeffrey Varnes , Haixia Wang , David M. Wilson , Dedong Wu , Ye Wu , Bin Yang , Wenzhan Yang Journal Of Medicinal Chemistry 63, 14530 - 14559 DOI: 10.1021/acs.jmedchem.0c01163 Show Abstract ▼ Abstract: Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.	Sep 2020
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion Sarah L. Kidd , Elaine Fowler , Till Reinhardt , Thomas Compton , Natalia Mateu , Hector Newman , Dom Bellini , Romain Talon , Joseph Mcloughlin , Tobias Krojer , Anthony Aimon , Anthony Bradley , Michael Fairhead , Paul Brear , Laura Diaz-Saez , Katherine Mcauley , Hannah F. Sore , Andrew Madin , Daniel H. O'Donovan , Kilian Huber , Marko Hyvonen , Frank Von Delft , Christopher G. Dowson , David R. Spring Chemical Science DOI: 10.1039/D0SC01232G Diamond Proposal Number(s): [18145, 15649, 14303, 14493] Open Access Show Abstract ▼ Abstract: Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10–14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.	May 2020
I04-1-Macromolecular Crystallography (fixed wavelength)	Rapid identification of novel allosteric PRC2 inhibitors Jon A. Read , Jonathan Tart , Philip B. Rawlins , Clare Gregson , Karen Jones , Ning Gao , Xiahui Zhu , Ron Tomlinson , Erin Code , Tony Cheung , Huawei Chen , Sameer P. Kawatkar , Andy Bloecher , Sharan Bagal , Daniel H. O’donovan , James Robinson Acs Chemical Biology DOI: 10.1021/acschembio.9b00468 Show Abstract ▼ Abstract: Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates chromatin state and gene expression by methylating histone H3 lysine 27. EZH2 is overexpressed or mutated in various hematological malignancies and solid cancers. Our previous efforts to identify inhibitors of PRC2 methyltransferase activity by high-throughput screening (HTS) resulted in large numbers of false positives and thus a significant hit deconvolution challenge. More recently, others have reported compounds that bind to another PRC2 core subunit, EED, and allosterically inhibit EZH2 activity. This mechanism is particularly appealing as it appears to retain potency in cell lines that have acquired resistance to orthosteric EZH2 inhibition. By designing a fluorescence polarization probe based on the reported EED binding compounds, we were able to quickly and cleanly re-triage our previously challenging HTS hit list and identify novel allosteric PRC2 inhibitors.	Sep 2019
I04-Macromolecular Crystallography	Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction Jessica Iegre , Paul Brear , David J. Baker , Yaw Sing Tan , Eleanor L. Atkinson , Hannah F. Sore , Daniel H. O'Donovan , Chandra S. Verma , Marko Hyvonen , David R. Spring Chemical Science 114 DOI: 10.1039/C9SC00798A Diamond Proposal Number(s): [18548] Open Access Show Abstract ▼ Abstract: The discovery of new Protein–Protein Interaction (PPI) modulators is currently limited by the difficulties associated with the design and synthesis of selective small molecule inhibitors. Peptides are a potential solution for disrupting PPIs; however, they typically suffer from poor stability in vivo and limited tissue penetration hampering their wide spread use as new chemical biology tools and potential therapeutics. In this work, a combination of CuAAC chemistry, molecular modelling, X-ray crystallography, and biological validation allowed us to develop highly functionalised peptide PPI inhibitors of the protein CK2. The lead peptide, CAM7117, prevents the formation of the holoenzyme assembly in vitro, slows down proliferation, induces apoptosis in cancer cells and is stable in human serum. CAM7117 could aid the development of novel CK2 inhibitors acting at the interface and help to fully understand the intracellular pathways involving CK2. Importantly, the approach adopted herein could be applied to many PPI targets and has the potential to ease the study of PPIs by efficiently providing access to functionalised peptides.	Apr 2019

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