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68 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Design of a potent and selective dual JAK1/TYK2 inhibitor Oscar Mammoliti , Christel Menet , Céline Cottereaux , Javier Blanc , Ann De Blieck , Ghjuvanni Coti , Raphaël Geney , Line Oste , Koen Ostyn , Adeline Palisse , Evelyne Quinton , Benoit Schmitt , Monica Borgonovi , Isabelle Parent , Catherine Jagerschmidt , Steve De Vos , Béatrice Vayssiere , Miriam López-Ramos , Kenji Shoji , Reginald Brys , David Amantini , René Galien , Caroline Joannesse Bioorganic & Medicinal Chemistry 114 DOI: 10.1016/j.bmc.2024.117932 Open Access Show Abstract ▼ Abstract: Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of TH1 and TH17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23-induced psoriasis-like inflammation mouse model.	Nov 2024
I04-Macromolecular Crystallography	Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study Nace Zidar , Andrej Emanuel Cotman , Wessel Sinnige , Ondrej Benek , Michaela Barančokova , Anamarija Zega , Lucija Peterlin Mašič , Tihomir Tomašič , Janez Ilaš , Sara R. Henderson , Julia E. A. Mundy , Anthony Maxwell , Clare E. M. Stevenson , David M. Lawson , Geert Jan Sterk , Rodrigo Tosso , Lucas Gutierrez , Ricardo D. Enriz , Danijel Kikelj Bioorganic & Medicinal Chemistry 43 DOI: 10.1016/j.bmc.2024.117798 Diamond Proposal Number(s): [18565] Open Access Show Abstract ▼ Abstract: N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.	Jun 2024
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Stereochemical inversion at a 1,4-cyclohexyl PROTAC linker fine-tunes conformation and binding affinity Martina Pierri , Xingui Liu , Alena Kroupova , Zoe Rutter , Alex J. Hallatt , Alessio Ciulli Bioorganic & Medicinal Chemistry Letters 21 DOI: 10.1016/j.bmcl.2024.129861 Diamond Proposal Number(s): [26793] Open Access Show Abstract ▼ Abstract: Proteolysis targeting chimeras (PROTACs) are heterobifunctional small-molecule degraders made of a linker connecting a target-binding moiety to a ubiquitin E3 ligase-binding moiety. The linker unit is known to influence the physicochemical and pharmacokinetic properties of PROTACs, as well as the properties of ternary complexes, in turn impacting on their degradation activity in cells and in vivo. Our LRRK2 PROTAC XL01126, bearing a trans-cyclohexyl group in the linker, is a better and more cooperative degrader than its corresponding cis- analogue despite its much weaker binary binding affinities. Here, we investigate how this subtle stereocenter alteration in the linker affects the ligand binding affinity to the E3 ligase VHL. We designed a series of molecular matched pairs, truncating from the full PROTACs down to the VHL ligand, and find that across the series the trans-cyclohexyl compounds showed consistently weaker VHL-binding affinity compared to the cis- counterparts. High-resolution co-crystal structures revealed that the trans linker exhibits a rigid stick-out conformation, while the cis linker collapses into a folded-back conformation featuring a network of intramolecular contacts and long-range interactions with VHL. These observations are noteworthy as they reveal how a single stereochemical inversion within a PROTAC linker impacts conformational rigidity and binding mode, in turn fine-tuning differentiated propensity to binary and ternary complex formation, and ultimately cellular degradation activity.	Jun 2024
I03-Macromolecular Crystallography	Synthesis and biological evaluation of 1H-pyrrolo[3,2–g]isoquinolines Mathilde Defois , Béatrice Josselin , Pierre Brindeau , Andreas Kramer , Stefan Knapp , Fabrice Anizon , Francis Giraud , Sandrine Ruchaud , Pascale Moreau Bioorganic & Medicinal Chemistry 100 DOI: 10.1016/j.bmc.2024.117619 Show Abstract ▼ Abstract: A structure–activity relationship study performed on 1H-pyrrolo[3,2–g]isoquinoline scaffold identified new haspin inhibitors with nanomolar potencies and selectivity indices (SI) over 6 (inhibitory potency evaluated against 8 protein kinases). Compound 22 was the most active of the series (haspin IC50 = 76 nM). Cellular evaluation of 22 confirmed its activity for endogenous haspin in U-2 OS cells and its anti-proliferative activity against various cell lines. In addition, the binding mode of analog 22 in complex with haspin was determined by X-ray crystallography.	Feb 2024
I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3 Brigitt Raux , Karly A. Buchan , James Bennett , Thomas Christott , Matthew S. Dowling , Gillian Farnie , Oleg Fedorov , Vicki Gamble , Carina Gileadi , Charline Giroud , Kilian V. M. Huber , Magdalena Korczynska , Chris Limberakis , Arjun Narayanan , Dafydd R. Owen , Laura Diaz Saez , Ingrid A. Stock , Allyn T. Londregan Bioorganic & Medicinal Chemistry Letters 87 DOI: 10.1016/j.bmcl.2023.129546 Show Abstract ▼ Abstract: Epigenetic proteins containing YEATS domains (YD) are an emerging target class in drug discovery. Described herein are the discovery and characterization efforts associated with PFI-6, a new chemical probe for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). For hit identification, fragment-like mimetics of endogenous YD ligands (crotonylated histone-containing proteins), were synthesized via parallel medicinal chemistry (PMC) and screened for MLLT1 binding. Subsequent SAR studies led to iterative MLLT1/3 binding and selectivity improvements, culminating in the discovery of PFI-6. PFI-6 demonstrates good affinity and selectivity for MLLT1/3 vs. other human YD proteins (YEATS2/4) and engages MLLT3 in cells. Small-molecule X-ray co-crystal structures of two molecules, including PFI-6, bound to the YD of MLLT1/3 are also described. PFI-6 may be a useful tool molecule to better understand the biological effects associated with modulation of MLLT1/3.	Nov 2023
I04-Macromolecular Crystallography	Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors Neil P. Grimster , Lakshmaiah Gingipalli , Amber Balazs , Bernard Barlaam , Scott Boiko , Scott Boyd , Hannah Dry , Frederick W. Goldberg , Tim Ikeda , Tony Johnson , Sameer Kawatkar , Paul Kemmitt , Scott Lamont , Olivier Lorthioir , Adelphe Mfuh , Joe Patel , Andy Pike , Jon Read , Romulo Romero , Ujjal Sarkar , Li Sha , Iain Simpson , Kun Song , Qibin Su , Haixia Wang , David Watson , Allan Wu , Troy E. Zehnder , Xiaolan Zheng , Shaolu Li , Zhiqiang Dong , Dejian Yang , Yanwei Song , Peng Wang , Xuemei Liu , James E. Dowling , Scott D. Edmondson Bioorganic & Medicinal Chemistry Letters 91 DOI: 10.1016/j.bmcl.2023.129352 Show Abstract ▼ Abstract: Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.	Jul 2023
I02-Macromolecular Crystallography	Filling a nick in NIK: Extending the half-life of a NIK inhibitor through structure-based drug design James J. Crawford , Jianwen Feng , Hans D. Brightbill , Adam R. Johnson , Matthew Wright , Aleksandr Kolesnikov , Wendy Lee , Georgette M. Castanedo , Steven Do , Nicole Blaquiere , Steven T. Staben , Po-Chang Chiang , Peter W. Fan , Matt Baumgardner , Susan Wong , Robert Godemann , Alice Grabbe , Catharina Wiegel , Swathi Sujatha-Bhaskar , Sarah G. Hymowitz , Nicholas Liau , Peter L. Hsu , Paul A. Mcewan , Moulay Hicham Alaoui Ismaili , Matthew L. Landry Bioorganic & Medicinal Chemistry Letters 89 DOI: 10.1016/j.bmcl.2023.129277 Show Abstract ▼ Abstract: Inhibition of NF-κB inducing kinase (NIK) has been pursued as a promising therapeutic target for autoimmune disorders due to its highly regulated role in key steps of the NF-κB signaling pathway. Previously reported NIK inhibitors from our group were shown to be potent, selective, and efficacious, but had higher human dose projections than desirable for immunology indications. Herein we report the clearance-driven optimization of a NIK inhibitor guided by metabolite identification studies and structure-based drug design. This led to the identification of an azabicyclo[3.1.0]hexanone motif that attenuated in vitro and in vivo clearance while maintaining NIK potency and increasing selectivity over other kinases, resulting in a greater than ten-fold reduction in predicted human dose.	Jun 2023
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery of a selective c-MET inhibitor with a novel binding mode Gavin W. Collie , Louise Barlind , Sana Bazzaz , Ulf Börjesson , Ian L. Dale , Jeremy S. Disch , Sevan Habeshian , Rachael Jetson , Puneet Khurana , Andrew Madin , Iacovos N. Michaelides , Ling Peng , Arjan Snijder , Christopher J. Stubbs Bioorganic & Medicinal Chemistry Letters 12 DOI: 10.1016/j.bmcl.2022.128948 Diamond Proposal Number(s): [17180, 20015] Open Access Show Abstract ▼ Abstract: The c-MET receptor tyrosine kinase has received considerable attention as a cancer drug target yet there remains a need for inhibitors which are selective for c-MET and able to target emerging drug-resistant mutants. We report here the discovery, by screening a DNA-encoded chemical library, of a highly selective c-MET inhibitor which was shown by X-ray crystallography to bind to the kinase in an unprecedented manner. These results represent a novel mode of inhibiting c-MET with a small molecule and may provide a route to targeting drug-resistant forms of the kinase whilst avoiding potential toxicity issues associated with broad kinome inhibition.	Aug 2022
I03-Macromolecular Crystallography	Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs Mirko M. Maksimainen , Sudarshan Murthy , Sven T. Sowa , Albert Galera-Prat , Elena Rolina , Juha P. Heiskanen , Lari Lehtio Bioorganic & Medicinal Chemistry 52 DOI: 10.1016/j.bmc.2021.116511 Diamond Proposal Number(s): [19951] Open Access Show Abstract ▼ Abstract: The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10–20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.	Dec 2021
I03-Macromolecular Crystallography	Identification of unprecedented ATP-competitive choline kinase inhibitors Francesca Quartieri , Marcella Nesi , Nilla R. Avanzi , Daniela Borghi , Elena Casale , Emiliana Corti , Ulisse Cucchi , Daniele Donati , Marina Fasolini , Eduard R. Felder , Arturo Galvani , Maria L. Giorgini , Antonio Lomolino , Maria Menichincheri , Christian Orrenius , Claudia Perrera , Stefania Re Depaolini , Federico Riccardi-Sirtori , Enea Salsi , Antonella Isacchi , Paola Gnocchi Bioorganic & Medicinal Chemistry Letters 51 DOI: 10.1016/j.bmcl.2021.128310 Diamond Proposal Number(s): [26586] Show Abstract ▼ Abstract: In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.	Nov 2021

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