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

Instruments / Technical Area	Publication Details	Published
I24-Microfocus Macromolecular Crystallography	Novel macrocyclic antagonists of the CGRP receptor part 2: stereochemical inversion induces an unprecedented binding mode Stacey M. Southall , Joydeep Banerjee , Jason Brown , Kristina Butkovic , Andrew D. Cansfield , Julie E. Cansfield , Miles S. Congreve , Gabriella Cseke , Francesca Deflorian , Martina Petrovic Hunjadi , Antun Hutinec , Trinadh Kumar Inturi , Renata Rupcic , Gordon Saxty , Stephen P. Watson Acs Medicinal Chemistry Letters 13, 1776 - 1782 DOI: 10.1021/acsmedchemlett.2c00400 Show Abstract ▼ Abstract: The diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 (3) and HTL0029882 (4), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that 3 binds to the CGRP receptor in a precedented manner but that 4 binds in an unprecedented, unexpected, and radically different manner. The observation of this phenomenon is noteworthy and may open novel avenues for CGRP receptor antagonist design.	Nov 2022
I24-Microfocus Macromolecular Crystallography	Identification of inhibitors of the Schistosoma mansoni VKR2 kinase domain Indran Mathavan , Lawrence J. Liu , Sean W. Robinson , Nelly El-Sakkary , Adam Jo J. Elatico , Darwin Gomez , Ricky Nellas , Raymond J. Owens , William Zuercher , Iva Navratilova , Conor R. Caffrey , Konstantinos Beis Acs Medicinal Chemistry Letters 77 DOI: 10.1021/acsmedchemlett.2c00248 Diamond Proposal Number(s): [12579] Open Access Show Abstract ▼ Abstract: Schistosomiasis is a neglected tropical disease caused by parasitic flatworms. Current treatment relies on just one partially effective drug, praziquantel (PZQ). Schistosoma mansoni Venus Kinase Receptors 1 and 2 (SmVKR1 and SmVKR2) are important for parasite growth and egg production, and are potential targets for combating schistosomiasis. VKRs consist of an extracellular Venus Flytrap Module (VFTM) linked via a transmembrane helix to a kinase domain. Here, we initiated a drug discovery effort to inhibit the activity of the SmVKR2 kinase domain (SmVKR2KD) by screening the GSK published kinase inhibitor set 2 (PKIS2). We identified several inhibitors, of which four were able to inhibit its enzymatic activity and induced phenotypic changes in ex vivoS. mansoni. Our crystal structure of the SmVKR2KD displays an active-like state that sheds light on the activation process of VKRs. Our data provide a basis for the further exploration of SmVKR2 as a possible drug target.	Oct 2022
I04-1-Macromolecular Crystallography (fixed wavelength)	Fragment-based discovery of a novel, brain penetrant, orally active HDAC2 inhibitor Emiliano Tamanini , Shin Miyamura , Ildiko M. Buck , Benjamin D. Cons , Lee Dawson , Charlotte East , Takashi Futamura , Shintaro Goto , Charlotte Griffiths-Jones , Tetsuya Hashimoto , Tom D. Heightman , Shunpei Ishikawa , Hideki Ito , Yosuke Kaneko , Tatsuya Kawato , Kazumi Kondo , Naoki Kurihara , James M. Mccarthy , Yukiko Mori , Tsuyoshi Nagase , Yuichiro Nakaishi , Judith Reeks , Akimasa Sato , Patrick Schöpf , Kuninori Tai , Taichi Tamai , Dominic Tisi , Alison J.-A. Woolford Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.2c00272 Show Abstract ▼ Abstract: Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein–ligand complex X-ray structures, into a sub-μM, brain penetrant, HDAC2 inhibitor (17) capable of modulating histone acetylation levels in vivo.	Sep 2022
I03-Macromolecular Crystallography	Optimization of hERG and pharmacokinetic properties for basic dihydro-8H-purin-8-one inhibitors of DNA-PK Frederick W. Goldberg , Attilla K. T. Ting , David Beattie , Gillian M. Lamont , Charlene Fallan , M. Raymond V. Finlay , Beth Williamson , Marianne Schimpl , Alexander R. Harmer , Oladipupo B. Adeyemi , Pär Nordell , Anna S. Cronin , Mercedes Vazquez-Chantada , Derek Barratt , Antonio Ramos-Montoya , Elaine B. Cadogan , Barry R. Davies Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.2c00172 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC50 = 10–15 μM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of pKa, to identify compound 18, which combines low hERG activity (IC50 = 75 μM) with excellent kinome selectivity and favorable pharmacokinetic properties.	Jul 2022
I03-Macromolecular Crystallography	Structure-guided design of D-galactal derivatives with high affinity and selectivity for the galectin-8 N-terminal domain Mujtaba Hassan , Floriane Baussière , Samo Guzelj , Anders P. Sundin , Maria Håkansson , Rebeka Kovačič , Hakon Leffler , Tihomir Tomašič , Marko Anderluh , Žiga Jakopin , Ulf J. Nilsson Acs Medicinal Chemistry Letters 12, 1745 - 1752 DOI: 10.1021/acsmedchemlett.1c00371 Diamond Proposal Number(s): [15916] Open Access Show Abstract ▼ Abstract: Galectin-8 is a carbohydrate-binding protein that plays a crucial role in tumor progression and metastasis, antibacterial autophagy, modulation of the immune system, and bone remodeling. The design, synthesis, and protein affinity evaluation of a set of C-3 substituted benzimidazole and quinoline d-galactal derivatives identified a d-galactal-benzimidazole hybrid as a selective ligand for the galectin-8 N-terminal domain (galectin-8N), with a Kd of 48 μM and 15-fold selectivity over galectin-3 and even better selectivity over the other mammalian galectins. X-ray structural analysis of galectin-8N in complex with one benzimidazole- and one quinoline-galactal derivative at 1.52 and 2.1 Å together with molecular dynamics simulations and quantum mechanical calculations of galectin-8N in complex with the benzimidazole derivative revealed orbital overlap between a NH LUMO of Arg45 with electron rich HOMOs of the olefin and O4 of the d-galactal. Such overlap is hypothesized to contribute to the high affinity of the d-galactal-derived ligands for galectin-8N. A (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay evaluation of the d-galactal-benzimidazole hybrid and an analogous galactoside derivative on a panel of cell lines with MTS assay showed no effect on cell viability up to 100 μM concentration. A subsequent functional assay using the MDA-MB-231 cell line demonstrated that the d-galactal-benzimidazole hybrid and the analogous galactoside derivative reduced the secretion of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in a dose-dependent manner. Therefore, these compounds represent potential probes for galectin-8N pharmacology investigations and possibly promising leads for the design and synthesis of potent and selective galectin-8 inhibitors as potential antitumor and anti-inflammatory agents.	Nov 2021
I04-1-Macromolecular Crystallography (fixed wavelength)	Carbamate and n-pyrimidine mitigate amide hydrolysis: Structure-based drug design of tetrahydroquinoline IDO1 inhibitors Derun Li , Yongqi Deng , Abdelghani Achab , Indu Bharathan , Brett Andrew Hopkins , Wensheng Yu , Hongjun Zhang , Sulagna Sanyal , Qinglin Pu , Hua Zhou , Kun Liu , Jongwon Lim , Xavier Fradera , Charles A. Lesburg , Alfred Lammens , Theodore A. Martinot , Ryan D. Cohen , Amy C. Doty , Heidi Ferguson , Elliott B. Nickbarg , Mangeng Cheng , Peter Spacciapoli , Prasanthi Geda , Xuelei Song , Nadya Smotrov , Pravien Abeywickrema , Christine Andrews , Chad Chamberlin , Omar Mabrouk , Patrick Curran , Matthew Richards , Peter Saradjian , J. Richard Miller , Ian Knemeyer , Karin M. Otte , Stella Vincent , Nunzio Sciammetta , Alexander Pasternak , David Jonathan Bennett , Yongxin Han Acs Medicinal Chemistry Letters 12, 389 - 396 DOI: 10.1021/acsmedchemlett.0c00525 Show Abstract ▼ Abstract: Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.	Mar 2021
I03-Macromolecular Crystallography	Discovery of diaminopyrimidine carboxamide HPK1 inhibitors as preclinical immunotherapy tool compounds Brandon A. Vara , Samuel M. Levi , Abdelghani Achab , David A. Candito , Xavier Fradera , Charles A. Lesburg , Shuhei Kawamura , Brian M. Lacey , Jongwon Lim , Joey L. Methot , Zangwei Xu , Haiyan Xu , Dustin M. Smith , Jennifer A. Piesvaux , J. Richard Miller , Mark Bittinger , Sheila H. Ranganath , David J. Bennett , Erin F. Dimauro , Alexander Pasternak Acs Medicinal Chemistry Letters 2 DOI: 10.1021/acsmedchemlett.1c00096 Show Abstract ▼ Abstract: Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure–activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.	Mar 2021
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structural basis for targeting the folded P-loop conformation of c-MET Gavin W. Collie , Iacovos N. Michaelides , Kevin Embrey , Christopher J. Stubbs , Ulf Börjesson , Ian L. Dale , Arjan Snijder , Louise Barlind , Kun Song , Puneet Khurana , Christopher Phillips , R. Ian Storer Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.0c00392 Open Access Show Abstract ▼ Abstract: We report here a fragment screen directed toward the c-MET kinase from which we discovered a series of inhibitors able to bind to a rare conformation of the protein in which the P-loop adopts a collapsed, or folded, arrangement. Preliminary SAR exploration led to an inhibitor (7) with nanomolar biochemical activity against c-MET and promising cell activity and kinase selectivity. These findings increase our structural understanding of the folded P-loop conformation of c-MET and provide a sound structural and chemical basis for further investigation of this underexplored yet potentially therapeutically exploitable conformational state.	Dec 2020
I04-Macromolecular Crystallography	The bicyclic form of galacto-noeurostegine is a potent inhibitor of β-galactocerebrosidase Agnete Viuff , Stéphane Salamone , Joseph Mcloughlin , Janet E. Deane , Henrik H. Jensen Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.0c00377 Diamond Proposal Number(s): [11235] Show Abstract ▼ Abstract: Competitive inhibitors of galactocerebrosidase (GALC) could be candidates for pharmacological chaperone therapy of patients with Krabbe disease. The known and selective nortropane-type iminosugar galacto-noeurostegine has been found to competitively inhibit GALC with Ki = 7 μM at pH 4.6, which is 330-fold more potent than the analogous deoxynoeurostegine. It was shown through X-ray protein crystallography that galacto-noeurostegine binds to the active site of GALC in its bicyclic form.	Dec 2020
I04-Macromolecular Crystallography	Exploring the chemical space of benzothiazole-based DNA gyrase B inhibitors Žiga Skok , Michaela Barančoková , Ondřej Benek , Cristina Durante Cruz , Päivi Tammela , Tihomir Tomašič , Nace Zidar , Lucija Peterlin Mašič , Anamarija Zega , Clare E. M. Stevenson , Julia E. A. Mundy , David M. Lawson , Anthony Maxwell , Danijel Kikelj , Janez Ilaš Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.0c00416 Diamond Proposal Number(s): [18565] Open Access Show Abstract ▼ Abstract: We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 μM), and efflux impaired E. coli strain (MIC = 0.78 μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.	Oct 2020

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