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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Covalent inhibitors of KEAP1 with exquisite selectivity Imre Fejes , Piroska Markacz , Janos Tatai , Monika Rudas , Petra Dunkel , Mario Gyuris , Miklos Nyerges , Nicolas Provost , Valérie Duvivier , Philippe Delerive , Virginie Martiny , Alexandra Bristiel , Brice Vidal , William Richardson , Elisabeth M. Rothweiler , Jeppe Tranberg-Jensen , Charlotte E. Manning , Melissa Sweeney , Rod Chalk , Kilian V. M. Huber , Alex N. Bullock , Andras Herner , Klaus Seedorf , Cedric Vinson , Csaba Weber , Andras Kotschy Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c02019 Diamond Proposal Number(s): [28172] Open Access Show Abstract ▼ Abstract: The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting with a phenotypic screen, we identified a new covalent inhibitor chemotype that was optimized to deliver a series of potent and highly selective KEAP1 binders. While the developed compounds showed both cellular and in vivo activity, upregulating antioxidant response element-dependent target genes, they showed no genotoxicity in vitro. The lead compound exhibited broad selectivity in activity-based protein profiling and showed no significant interaction with a panel of commonly studied receptors nor with a broad panel of kinases. The nature of its interaction with KEAP1 and the origin of its selectivity were revealed by X-ray crystallography.	Nov 2024
	Toward target 2035: EUbOPEN - a public-private partnership to enable & unlock biology in the open Claudia Tredup , Suzanne Ackloo , Hartmut Beck , Peter J. Brown , Alex N. Bullock , Alessio Ciulli , Ivan Dikic , Kristina Edfeldt , Aled M. Edwards , Jonathan M. Elkins , Henner F. Farin , Edward A. Fon , Matthias Gstaiger , Judith Günther , Anna-Lena Gustavsson , Sandra Häberle , Laura Isigkeit , Kilian V. M. Huber , Andras Kotschy , Oliver Krämer , Andrew R. Leach , Brian D. Marsden , Hisanori Matsui , Daniel Merk , Florian Montel , Monique P. C. Mulder , Susanne Müller , Dafydd R. Owen , Ewgenij Proschak , Sandra Röhm , Alexandra Stolz , Michael Sundström , Frank Von Delft , Timothy M. Willson , Cheryl H. Arrowsmith , Stefan Knapp Rsc Medicinal Chemistry 11 DOI: 10.1039/D4MD00735B Open Access Show Abstract ▼ Abstract: Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public–private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents. The substantial outputs of this programme include a chemogenomic compound library covering one third of the druggable proteome, as well as 100 chemical probes, both profiled in patient derived assays, as well as hundreds of data sets deposited in existing public data repositories and a project-specific data resource for exploring EUbOPEN outputs.	Nov 2024
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Structure-guided discovery of selective USP7 inhibitors with in vivo activity Attila Vasas , Lisa Ivanschitz , Balázs Molnár , Árpád Kiss , Lisa Baker , Andrea Fiumana , Alba Macias , James B. Murray , Emma Sanders , Neil Whitehead , Roderick E. Hubbard , Carine Saunier , Elodie Monceau , Anne Marie Girard , Marion Rousseau , Maia Chanrion , Didier Demarles , Olivier Geneste , Csaba Weber , Elodie Lewkowicz , Andras Kotschy Journal Of Medicinal Chemistry 2 DOI: 10.1021/acs.jmedchem.4c01472 Diamond Proposal Number(s): [5791, 6001, 5067] Show Abstract ▼ Abstract: Inhibition of ubiquitin-specific protease 7, USP7, has been proposed as a mechanism to affect many disease processes, primarily those implicated in oncology. The bound crystal structure of a published high-throughput screening hit with low-micromolar affinity for USP7 identified three regions of the compound for structure-guided optimization. Replacing one side of the compound with different aromatic moieties gave little improvement in affinity, and the central piperidine could not be improved. However, the binding site for the other side of the compound was poorly defined in the crystal structure, which suggested a wide variety of synthetically accessible options for optimization. These were assessed by screening reaction mixtures that introduced different substituents to this other side. Subsequent optimization led to a compound with low-nanomolar affinity for USP7, which showed target engagement in tumors, was tolerated in mice, and showed efficacy in xenograft models.	Oct 2024
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	The effect of core replacement on S64315, a selective MCL-1 inhibitor, and its analogues Szabolcs Sipos , Balázs Bálint , Zoltán B. Szabó , Levente Ondi , Márton Csékei , Zoltán Szlávik , Ágnes Proszenyák , James B. Murray , James Davidson , Ijen Chen , Pawel Dokurno , Allan E. Surgenor , Christopher Pedder , Roderick E. Hubbard , Ana-Leticia Maragno , Maia Chanrion , Frederic Colland , Olivier Geneste , András Kotschy Acs Omega 6, 22073 - 22102 DOI: 10.1021/acsomega.1c02595 Diamond Proposal Number(s): [1857] Open Access Show Abstract ▼ Abstract: Following the identification of thieno[2,3-d]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent core replacement analogues showed considerable in vivo PD response. One compound was progressed into efficacy studies and inhibited tumor growth.	Aug 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Fragment-derived selective inhibitors of dual-specificity kinases DYRK1A and DYRK1B David Lee Walmsley , James B. Murray , Pawel Dokurno , Andrew J. Massey , Karen Benwell , Andrea Fiumana , Nicolas Foloppe , Stuart Ray , Julia Smith , Allan E. Surgenor , Thomas Edmonds , Didier Demarles , Mike Burbridge , Francisco Cruzalegui , Andras Kotschy , Roderick E. Hubbard Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00024 Open Access Show Abstract ▼ Abstract: The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down’s syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.	Jun 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structure-guided discovery of potent and selective DYRK1A inhibitors Csaba Weber , Melinda Sipos , Attila Paczal , Balazs Balint , Vilibald Kun , Nicolas Foloppe , Pawel Dokurno , Andrew J. Massey , David Lee Walmsley , Roderick E. Hubbard , James Murray , Karen Benwell , Thomas Edmonds , Didier Demarles , Alain Bruno , Mike Burbridge , Francisco Cruzalegui , Andras Kotschy Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00023 Diamond Proposal Number(s): [1857, 2103] Show Abstract ▼ Abstract: The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.	May 2021
I02-Macromolecular Crystallography	Discovery of S64315, a potent and selective Mcl-1 inhibitor Zoltan Szlavik , Marton Csekei , Attila Paczal , Zoltan B. Szabo , Szabolcs Sipos , Gabor Radics , Agnes Proszenyak , Balazs Balint , James Murray , James Davidson , Ijen Chen , Pawel Dokurno , Allan E Surgenor , Zoe Marie Daniels , Roderick E. Hubbard , Gaëtane Le Toumelin-Braizat , Audrey Claperon , Gaëlle Lysiak-Auvity , Anne-Marie Girard , Alain Bruno , Maia Chanrion , Frédéric Colland , Ana-Leticia Maragno , Didier Demarles , Olivier Geneste , Andras Kotschy Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01234 Diamond Proposal Number(s): [2103] Show Abstract ▼ Abstract: Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.	Nov 2020
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-guided discovery of a selective Mcl-1 inhibitor with cellular activity Zoltan Szlávik , Levente Ondi , Márton Csékei , Attila Paczal , Zoltán B. Szabó , Gábor Radics , James Murray , James Davidson , Ijen Chen , Ben Davis , Roderick E. Hubbard , Christopher Pedder , Pawel Dokurno , Allan Surgenor , Julia Smith , Alan Robertson , Gaetane Letoumelin-Braizat , Nicolas Cauquil , Marion Zarka , Didier Demarles , Francoise Perron-Sierra , Audrey Claperon , Frederic Colland , Olivier Geneste , András Kotschy Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00134 Diamond Proposal Number(s): [17182, 1194, 2103] Show Abstract ▼ Abstract: Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.	Jul 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Establishing drug discovery and identification of hit series for the anti-apoptotic proteins, Bcl-2 and Mcl-1 James B. Murray , James Davidson , Ijen Chen , Ben Davis , Pawel Dokurno , Christopher J. Graham , Richard Harris , Allan Jordan , Natalia Matassova , Christopher Pedder , Stuart Ray , Stephen D. Roughley , Julia Smith , Claire Walmsley , Yikang Wang , Neil Whitehead , Douglas S. Williamson , Patrick Casara , Thierry Le Diguarher , John Hickman , Jerome Stark , András Kotschy , Olivier Geneste , Roderick E. Hubbard Acs Omega 4, 8892 - 8906 DOI: 10.1021/acsomega.9b00611 Diamond Proposal Number(s): [671, 1194, 17182] Open Access Show Abstract ▼ Abstract: We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a Kd of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.	May 2019

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