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

Instruments / Technical Area	Publication Details	Published
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
I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of CA-4948, an orally bioavailable IRAK4 inhibitor for treatment of hematologic malignancies Venkateshwar Rao Gummadi , Anima Boruah , Bharathi Raja Ainan , Brahma Reddy Vare , Srinivas Manda , Hari Prakash Gondle , Shiva Nagendra Kumar , Subhendu Mukherjee , Suraj T. Gore , Narasimha Rao Krishnamurthy , Sivapriya Marappan , Shilpa S. Nayak , Kavitha Nellore , Wesley Roy Balasubramanian , Archana Bhumireddy , Sanjeev Giri , Sreevalsam Gopinath , Dodheri S. Samiulla , Girish Daginakatte , Aravind Basavaraju , Shekar Chelur , Rajesh Eswarappa , Charamanna Belliappa , Hosahalli S. Subramanya , Robert N. Booher , Murali Ramachandra , Susanta Samajdar Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.0c00255 Show Abstract ▼ Abstract: Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene’s compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia.	Oct 2020
I03-Macromolecular Crystallography	Mining public domain data to develop selective DYRK1A inhibitors Scott H. Henderson , Fiona Sorrell , James Bennett , Marcus T. Hanley , Sean Robinson , Iva Hopkins Navratilova , Jonathan M. Elkins , Simon E. Ward Acs Medicinal Chemistry Letters 11, 1620 - 1626 DOI: 10.1021/acsmedchemlett.0c00279 Diamond Proposal Number(s): [15433] Open Access Show Abstract ▼ Abstract: Kinases represent one of the most intensively pursued groups of targets in modern-day drug discovery. Often it is desirable to achieve selective inhibition of the kinase of interest over the remaining ∼500 kinases in the human kinome. This is especially true when inhibitors are intended to be used to study the biology of the target of interest. We present a pipeline of open-source software that analyzes public domain data to repurpose compounds that have been used in previous kinase inhibitor development projects. We define the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) as the kinase of interest, and by addition of a single methyl group to the chosen starting point we remove glycogen synthase kinase β (GSK3β) and cyclin-dependent kinase (CDK) inhibition. Thus, in an efficient manner we repurpose a GSK3β/CDK chemotype to deliver 8b, a highly selective DYRK1A inhibitor.	Aug 2020
I04-Macromolecular Crystallography	Design and development of a macrocyclic series targeting phosphoinositide 3-kinase δ Jonathan A. Spencer , Ian R. Baldwin , Nick Barton , Chun-Wa Chung , Máire A. Convery , Christopher D. Edwards , Craig Jamieson , David N. Mallett , James E. Rowedder , Paul Rowland , Daniel A. Thomas , Charlotte J. Hardy Acs Medicinal Chemistry Letters 11, 1386 - 1391 DOI: 10.1021/acsmedchemlett.0c00061 Show Abstract ▼ Abstract: A macrocyclization approach has been explored on a series of benzoxazine phosphoinositide 3-kinase δ inhibitors, resulting in compounds with improved potency, permeability, and in vivo clearance while maintaining good solubility. The thermodynamics of binding was explored via surface plasmon resonance, and the binding of lead macrocycle 19 was found to be almost exclusively entropically driven compared with progenitor 18, which demonstrated both enthalpic and entropic contributions. The pharmacokinetics of macrocycle 19 was also explored in vivo, where it showed reduced clearance when compared with the progenitor 18. This work adds to the growing body of evidence that macrocyclization could provide an alternative and complementary approach to the design of small-molecule inhibitors, with the potential to deliver differentiated properties.	Jul 2020

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