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18 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2 [Next/Last]

Instruments / Technical Area	Publication Details	Published
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
I04-1-Macromolecular Crystallography (fixed wavelength)	A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase Naoki Kuki , David L. Walmsley , Kazuo Kanai , Sho Takechi , Masao Yoshida , Ryo Murakami , Kohei Takano , Yuichi Tominaga , Mizuki Takahashi , Shuichiro Ito , Naoki Nakao , Hayley Angove , Lisa M. Baker , Edward Carter , Pawel Dokurno , Loic Le Strat , Alba T. Macias , Carrie-Anne Molyneaux , James B. Murray , Allan E. Surgenor , Tomoaki Hamada , Roderick E. Hubbard Rsc Medicinal Chemistry 14, 2731 - 2737 DOI: 10.1039/D3MD00439B Show Abstract ▼ Abstract: Several generations of ATP-competitive anti-cancer drugs that inhibit the activity of the intracellular kinase domain of the epidermal growth factor receptor (EGFR) have been developed over the past twenty years. The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket. Resistance emerges through mutation of the T790 gatekeeper residue to methionine, which introduces steric hindrance to drug binding and increases the Km for ATP. A third generation of drugs, such as osimertinib were developed which were effective against T790M EGFR in which an acrylamide moiety forms a covalent bond with C797, although resistance has emerged by mutation to S797. A fragment-based screen to identify new starting points for an EGFR inhibitor serendipitously identified a fragment that reacted with C775, a previously unexploited residue in the ATP binding pocket for a covalent inhibitor to target. A number of acrylamide containing fragments were identified that selectively reacted with C775. One of these acrylamides was optimized to a highly selective inhibitor with sub-1 μM activity, that is active against T790M, C797S mutant EGFR independent of ATP concentration, providing a potential new strategy for pan-EGFR mutant inhibition.	Dec 2023
	Fragment merging using a graph database samples different catalogue space than similarity search Stephanie Wills , Ruben Sanchez-Garcia , Tim Dudgeon , Stephen D. Roughley , Andy Merritt , Roderick E. Hubbard , James Davidson , Frank Von Delft , Charlotte M. Deane Journal Of Chemical Information And Modeling 9 DOI: 10.1021/acs.jcim.3c00276 Open Access Show Abstract ▼ Abstract: Fragment merging is a promising approach to progressing fragments directly to on-scale potency: each designed compound incorporates the structural motifs of overlapping fragments in a way that ensures compounds recapitulate multiple high-quality interactions. Searching commercial catalogues provides one useful way to quickly and cheaply identify such merges and circumvents the challenge of synthetic accessibility, provided they can be readily identified. Here, we demonstrate that the Fragment Network, a graph database that provides a novel way to explore the chemical space surrounding fragment hits, is well-suited to this challenge. We use an iteration of the database containing >120 million catalogue compounds to find fragment merges for four crystallographic screening campaigns and contrast the results with a traditional fingerprint-based similarity search. The two approaches identify complementary sets of merges that recapitulate the observed fragment–protein interactions but lie in different regions of chemical space. We further show our methodology is an effective route to achieving on-scale potency by retrospective analyses for two different targets; in analyses of public COVID Moonshot and Mycobacterium tuberculosis EthR inhibitors, potential inhibitors with micromolar IC50 values were identified. This work demonstrates the use of the Fragment Network to increase the yield of fragment merges beyond that of a classical catalogue search.	May 2023
I03-Macromolecular Crystallography	PAC-FragmentDEL – photoactivated covalent capture of DNA-encoded fragments for hit discovery Huiyong Ma , James B. Murray , Huadong Luo , Xuemin Cheng , Qiuxia Chen , Chao Song , Cong Duan , Ping Tan , Lifang Zhang , Jian Liu , Barry A. Morgan , Jin Li , Jinqiao Wan , Lisa M. Baker , William Finnie , Lucie Guetzoyan , Richard Harris , Nicole Hendrickson , Natalia Matassova , Heather Simmonite , Julia Smith , Roderick E. Hubbard , Guansai Liu Rsc Medicinal Chemistry 15 DOI: 10.1039/D2MD00197G Diamond Proposal Number(s): [29348] Open Access Show Abstract ▼ Abstract: We describe a novel approach for screening fragments against a protein that combines the sensitivity of DNA-encoded library technology with the ability of fragments to explore what will bind. Each of the members of the library consists of a fragment which is linked to a photoactivatable diazirine moiety. Split and pool synthesis combines each fragment with a set of linkers with the version of the library reported here containing some 70k different compounds, each with an individual DNA code. Incubation of the library with a protein sample is followed by photoactivation, washing and subsequent PCR and sequencing which allows the individual fragment hits to be identified. We illustrate how the approach allows successful hit fragment identification using only microgram quantities of material for two targets. PAK4 is a kinase for which conventional fragment screening has generated many advance leads. The as yet undrugged target, 2-epimerase, presents a more challenging active site for identification of hit compounds. In both cases, PAC-FragmentDEL identified fragments validated as hits by ligand-observed NMR measurements and crystal structure determination of off-DNA sample binding to the proteins.	Aug 2022
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 I04-Macromolecular Crystallography	Fragment-based discovery of novel non-hydroxamate LpxC inhibitors with antibacterial activity Yousuke Yamada , Hajime Takashima , David Lee Walmsley , Fumihito Ushiyama , Yohei Matsuda , Harumi Kanazawa , Toru Yamaguchi-Sasaki , Nozomi Tanaka-Yamamoto , Junya Yamagishi , Risa Kurimoto-Tsuruta , Yuya Ogata , Norikazu Ohtake , Hayley Angove , Lisa Baker , Richard Harris , Alba Macias , Alan Robertson , Allan Surgenor , Hayato Watanabe , Koichiro Nakano , Masashi Mima , Kunihiko Iwamoto , Atsushi Okada , Iichiro Takata , Kosuke Hitaka , Akihiro Tanaka , Kiyoko Fujita , Hiroyuki Sugiyama , Roderick E. Hubbard Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01215 Diamond Proposal Number(s): [12428] Open Access Show Abstract ▼ Abstract: UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.	Nov 2020
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
I04-1-Macromolecular Crystallography (fixed wavelength)	Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures Lisa M. Baker , Anthony Aimon , James B. Murray , Allan E. Surgenor , Natalia Matassova , Stephen D. Roughley , Patrick M. Collins , Tobias Krojer , Frank Von Delft , Roderick E. Hubbard Communications Chemistry 3 DOI: 10.1038/s42004-020-00367-0 Open Access Show Abstract ▼ Abstract: Fragment based methods are now widely used to identify starting points in drug discovery and generation of tools for chemical biology. A significant challenge is optimization of these weak binding fragments to hit and lead compounds. We have developed an approach where individual reaction mixtures of analogues of hits can be evaluated without purification of the product. Here, we describe experiments to optimise the processes and then assess such mixtures in the high throughput crystal structure determination facility, XChem. Diffraction data for crystals of the proteins Hsp90 and PDHK2 soaked individually with 83 crude reaction mixtures are analysed manually or with the automated XChem procedures. The results of structural analysis are compared with binding measurements from other biophysical techniques. This approach can transform early hit to lead optimisation and the lessons learnt from this study provide a protocol that can be used by the community.	Sep 2020

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