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Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Discovery of small-molecule ligands for the E3 ligase STUB1/CHIP from a DNA-encoded library screen Simon C. C. Lucas , Alexander G. Milbradt , Jason Breed , Erwin De Genst , Anne Jackson , Alisa Solovyeva , Bryony Ackroyd , Matthias R. Bauer , Juntai Liu , David Longmire , Dušan Petrović , Emma L. Rivers , Christopher Stubbs , Poppy Winlow , Sana Bazzaz , Paige Dickson , Diana Gikunju , Marie-Aude Guié , John P. Guilinger , Christopher D. Hupp , Rachael Jetson , Anthony D. Keefe , Katherine Nugai , John T. S. Yeoman , Ying Zhang , Xian Feng , Dequan Yu , Christopher Phillips Acs Medicinal Chemistry Letters 16, 1445 - 1451 DOI: 10.1021/acsmedchemlett.5c00361 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: STIP1 homology and U-box containing protein 1 (STUB1), also known as the C-terminus of Hsc70-interacting protein (CHIP), is an E3 ligase that plays a crucial role in removal of misfolded proteins via Hsc70. A DEL screen was run against CHIP to identify small-molecule binders. Two hits were identified that were confirmed by biochemical and biophysical techniques, including 2D NMR. X-ray crystal structures were obtained, which revealed binding to the peptide binding site. Fragment-based deconstruction indicated that hit 2 was a suitable starting point for optimization. During the optimization, an unexpected rearrangement of an oxadiazole from an array hit led to the exploration of an amide vector. This resulted in the discovery of compound 5, which is the most potent small-molecule ligand for CHIP identified to date and a suitable starting point for further optimization into a tool molecule or PROTAC warhead.	Aug 2025
I03-Macromolecular Crystallography	Discovery of pyrimidoindolones as novel family VIII bromodomain binders Jeffrey A. Boerth , Marianne Schimpl , Simon C. C. Lucas , Jingwen Zhang , Erin L. Code , Kevin J. Embrey , Philip B. Rawlins , Haixia Wang , R. Ian Storer , Paolo Di Fruscia , Jennifer E. Nelson , Alexander G. Milbradt , Ulf Börjesson , Andrea Gohlke , Victoria Korboukh , Ariamala Gopalsamy Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.5c00120 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Suppression of oncogenic gene expression is an effective strategy for the treatment of cancer. The SWI/SNF (SWItch/Sucrose Non-Fermentable) complex plays an important role in regulating gene activation or repression, and its dysregulation has been linked to aberrant transcription activity in many types of cancer. Targeting the subunits of this complex, such as SMARCA2, SMARCA4, and PBRM1, which are part of the bromodomain family VIII, has significant therapeutic potential. Herein we report the discovery of pyrimidoindolones as a novel series of bromodomain family VIII binders identified through an NMR-based fragment screen. These binders have been optimized to achieve sub-μM affinity for the family VIII proteins SMARCA2, SMARCA4, and PRBM1, with promising physicochemical properties.	May 2025
I04-Macromolecular Crystallography	Discovery of a series of covalent ligands that bind to Cys77 of the Von Hippel–Lindau Tumor Suppressor Protein (VHL) Simon C. C. Lucas , Yong Xu , Sarah Hewitt , Gavin W. Collie , Lucia Fusani , Ganesh Kadamur , Thomas E. Hadfield , Nancy Su , Caroline Truman , Sylvain Demanze , Haie Hao , Christopher Phillips Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.4c00582 Show Abstract ▼ Abstract: Most ligands for the Von Hippel–Lindau tumor suppressor (VHL) bind at the HIF-1α binding site. Ligands that bind to allosteric sites on VHL could be highly valuable for the field of protein degradation, therefore, a covalent hit identification campaign was run targeting Cys77 on VHL. Hit 2 bound selectively to Cys77 on VHL and did not alkylate the reactive Cys89 on Elongin B. It showed time- and concentration-dependent labeling, with a kinact/KI of 0.30 M–1 s–1, and does not affect binding at the HIF-1α site. This hit ligand was optimized to afford compound 15 which showed improved potency and labeling of VHL. An X-ray structure of a close analogue was determined revealing the compound binding in a shallow groove on the surface of VHL. These are the first small molecules that bind covalently to an allosteric site on VHL and provide a suitable starting point for further optimization.	Mar 2025
I04-Macromolecular Crystallography	Structure-based discovery of a series of covalent, orally bioavailable, and selective BFL1 inhibitors Adeline Palisse , Tony Cheung , Aileen Blokhuis , Thomas Cogswell , Bruna S. Martins , Rick Riemens , Rick Schellekens , Giovanni Battocchio , Chimed Jansen , Matthew A. Cottee , Kimberly Ornell , Claudia Sacchetto , Leonardo Leon , Maaike Van Hoek-Emmelot , Mark Bostock , Brooke Leann Brauer , Kevin Beaumont , Simon C. C. Lucas , Samiyah Ahmed , J. Henry Blackwell , Ulf Börjesson , Andrea Gohlke , Iva Monique T. Gramatikov , David Hargreaves , Vera Van Hoeven , Vasudev Kantae , Lea Kupcova , Alexander G. Milbradt , Uthpala Seneviratne , Nancy Su , John Vales , Haiyun Wang , Michael J. White , Olaf Kinzel Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c01995 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: BFL1, a member of the antiapoptotic BCL2 family, has been relatively understudied compared to its counterparts despite evidence of its overexpression in various hematological malignancies. Across two articles, we describe the development of BFL1 in vivo tools. The first article describes the hit identification from a covalent fragment library and the subsequent evolution from the hit to compound 6.22 This work reports the structure-based optimization of compound 6 into a series of BFL1 inhibitors selective over the other BCL2 family members, with low nanomolar cellular activity when combined with AZD5991, exemplified by compound 20. Compound 20 demonstrated a cell death phenotype in SUDHL1 and OCILY10 cell lines and in the in vivo study, BFL1 stabilization and cleaved caspase 3 activation were observed in a dose-dependent manner. In addition, the enzymatic turnover studies with the BFL1 protein showed that compound 20 stabilized the protein, extending the half-life to 10.8 h.	Dec 2024
I04-Macromolecular Crystallography	Structure-based optimization of a series of covalent, cell active Bfl-1 inhibitors Simon C. C. Lucas , J. Henry Blackwell , Ulf Börjesson , David Hargreaves , Alexander G. Milbradt , Mark J. Bostock , Samiyah Ahmed , Kevin Beaumont , Tony Cheung , Sylvain Demanze , Andrea Gohlke , Carine Guerot , Afreen Haider , Vasudev Kantae , Gregory W. Kauffman , Olaf Kinzel , Lea Kupcova , Michael D. Lainchbury , Michelle L. Lamb , Leonardo Leon , Adeline Palisse , Claudia Sacchetto , R. Ian Storer , Nancy Su , Clare Thomson , John Vales , Yunhua Chen , Xiaolong Hu Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c01288 Show Abstract ▼ Abstract: Bfl-1, a member of the Bcl-2 family of proteins, plays a crucial role in apoptosis regulation and has been implicated in cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 represents a promising strategy for cancer treatment. Herein, the optimization of a covalent cellular tool from a lead-like hit using structure based design is described. Informed by a reversible X-ray fragment screen, the strategy to establish interactions with a key glutamic acid residue (Glu78) and optimize binding in a cryptic pocket led to a 1000-fold improvement in biochemical potency without increasing reactivity of the warhead. Compound (R,R,S)-26 has a kinact/KI of 4600 M–1 s–1, shows <1 μM caspase activation in a cellular assay and cellular target engagement, and has good physicochemical properties and a promising in vivo profile.	Sep 2024
I04-Macromolecular Crystallography	Design of a lead-like cysteine-targeting covalent library and the identification of hits to Cys55 of Bfl-1 Simon C. C. Lucas , Alexander G. Milbradt , J. Henry Blackwell , Silvia Bonomo , Andrew Brierley , Doyle J. Cassar , Jared Freeman , Thomas E. Hadfield , Lucas A. Morrill , Rick Riemens , Sunil Sarda , Stefan Schiesser , Daniel Wiktelius , Samiyah Ahmed , Mark J. Bostock , Ulf Börjesson , Claudia De Fusco , Carine Guerot , David Hargreaves , Sarah Hewitt , Michelle L. Lamb , Nancy Su , Ryan Whatling , Matthew Wheeler , Jason G. Kettle Journal Of Medicinal Chemistry 49 DOI: 10.1021/acs.jmedchem.4c00781 Show Abstract ▼ Abstract: Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space. Herein, the approach taken to build a library of 12k covalent lead-like compounds is reported, utilizing legacy compounds, robust library chemistry, and acquisitions. The lead-like covalent library was screened against the antiapoptotic protein Bfl-1, and six promising hits that displaced the BIM peptide from the PPI interface were identified. Intriguingly, X-ray crystallography of lead-like compound 8 showed that it binds to a previously unobserved conformation of the Bfl-1 protein and is an ideal starting point for the optimization of Bfl-1 inhibitors.	Jun 2024
I04-Macromolecular Crystallography	Identification and evaluation of reversible covalent binders to Cys55 of Bfl-1 from a DNA-encoded chemical library screen Simon C. C. Lucas , J. Henry Blackwell , Ulf Börjesson , David Hargreaves , Alexander G. Milbradt , Samiyah Ahmed , Mark J. Bostock , Carine Guerot , Andrea Gohlke , Olaf Kinzel , Michelle L. Lamb , Nidhal Selmi , Christopher J. Stubbs , Nancy Su , Qibin Su , Haiou Luo , Ting Xiong , Xiaoqian Zuo , Sana Bazzaz , Corey Bienstock , Paolo A. Centrella , Kyle E. Denton , Diana Gikunju , Marie-Aude Guié , John P. Guilinger , Christopher Hupp , Anthony D. Keefe , Takashi Satoh , Ying Zhang , Emma L. Rivers Acs Medicinal Chemistry Letters 15, 791 - 797 DOI: 10.1021/acsmedchemlett.4c00113 Show Abstract ▼ Abstract: Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.	Jun 2024
I02-Macromolecular Crystallography	Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors Simon C. C. Lucas , Stephen J. Atkinson , Chun-Wa Chung , Rob Davis , Laurie Gordon , Paola Grandi , James J. R. Gray , Thomas Grimes , Alexander Phillipou , Alex G. Preston , Rab K. Prinjha , Inmaculada Rioja , Simon Taylor , Nicholas C. O. Tomkinson , Ian Wall , Robert J. Watson , James Woolven , Emmanuel H. Demont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00344 Show Abstract ▼ Abstract: Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.	Jul 2021
I04-Macromolecular Crystallography	Optimisation of potent ATAD2 and CECR2 bromodomain inhibitors with an atypical binding mode Simon Lucas , Stephen J. Atkinson , Paul Bamborough , Heather A. Barnett , Chun-Wa Chung , Laurie J. Gordon , Darren J. Mitchell , Alexander Phillipou , Rab K. Prinjha , Robert J. Sheppard , Nicholas C. O. Tomkinson , Robert J. Watson , Emmanuel H. Demont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00021 Show Abstract ▼ Abstract: Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimisation of a series of phenyl sulfonamides which exhibit a novel mode of binding to non-Bromodomain and Extra Terminal Domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule we report its divergent optimisation towards the ATPase family AAA domain containing 2 (ATAD2) and Cats Eye Syndrome Chromosome Region, Candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.	Apr 2020
I02-Macromolecular Crystallography	A qualified success: discovery of a new series of ATAD2 bromodomain inhibitors with a novel binding mode using high-throughput screening and hit qualification Paul Bamborough , Chun-Wa Chung , Emmanuel H. Demont , Angela M. Bridges , Peter D. Craggs , David P. Dixon , Peter Francis , Rebecca C. Furze , Paola Grandi , Emma J. Jones , Bhumika Karamshi , Kelly Locke , Simon C. C. Lucas , Anne-Marie Michon , Darren J. Mitchell , Peter Pogány , Rab K. Prinjha , Christina Rau , Ana Maria Roa , Andrew D. Roberts , Robert J. Sheppard , Robert J. Watson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00673 Show Abstract ▼ Abstract: The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure–activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.	Aug 2019

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