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

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	A chemical probe targeting AAK1 and BMP2K Carrow Wells , Rafael M. Counago , Juanita C. Limas , Tuanny L. Almeida , Jeanette Gowen Cook , David H Drewry , Jonathan M. Elkins , Opher Gileadi , Nirav R. Kapadia , Alvaro Lorente-macias , Julie E. Pickett , Alexander Riemen , Roberta R. Ruela-de-sousa , Timothy M. Willson , Cunyu Zhang , William J Zuercher , Reena Zutshi , Alison D. Axtman Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.9b00399 Diamond Proposal Number(s): [14664] Show Abstract ▼ Abstract: Inhibitors based on a 3-acylaminoindazole scaffold were synthesized to yield potent dual AAK1/BMP2K inhibitors. Optimization furnished a small molecule chemical probe (SGC-AAK1-1, 25) that is potent and selective for AAK1/BMP2K over other NAK family members, demonstrates narrow activity in a kinome-wide screen, and is functionally active in cells. This inhibitor represents one of the best available small molecule tools to study the functions of AAK1 and BMP2K.	Oct 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Building bridges in a series of estrogen receptor degraders: an application of metathesis in medicinal chemistry James S. Scott , Jason Breed , Rodrigo J. Carbajo , Paul R. Davey , Ryan Greenwood , Hoan K. Huynh , Teresa Klinowska , Christopher J. Morrow , Thomas A. Moss , Radoslaw Polanski , J. Willem M. Nissink , Jeffrey Varnes , Bin Yang Acs Medicinal Chemistry Letters 10, 1492 - 1497 DOI: 10.1021/acsmedchemlett.9b00370 Diamond Proposal Number(s): [20015, 17180] Show Abstract ▼ Abstract: Herein we report the use of metathesis to construct a novel tetracyclic core in a series of estrogen receptor degraders. This improved the chemical stability, as assessed using an NMR-MS based assay, and gave a molecule with excellent physicochemical properties and pharmacokinetics in rat. X-ray crystallography established minimal perturbation of the bridged compounds relative to the unbridged analogues in the receptor binding pocket. Unfortunately, despite retaining excellent binding to ERα, this adversely affected the ability of the compounds to degrade the receptor.	Sep 2019
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structural and molecular insight into resistance mechanisms of first generation cMET inhibitors Gavin W. Collie , Cheryl M. Koh , Daniel J. O'neill , Christopher J. Stubbs , Puneet Khurana , Alice Eddershaw , Arjan Snijder , Fredrik Mauritzson , Louise Barlind , Ian L. Dale , Joseph Shaw , Christopher Phillips , Edward J. Hennessy , Tony Cheung , Ana J. Narvaez Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.9b00276 Diamond Proposal Number(s): [14631] Show Abstract ▼ Abstract: Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Towards this end we report here the first crystal structures of the recent clinically-observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase which could have implications for small molecule in-hibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.	Aug 2019
I04-1-Macromolecular Crystallography (fixed wavelength)	Structure based design of potent selective inhibitors of protein kinase D1 (PKD1) Jianwen A. Feng , Patrick Lee , Moulay Hicham Alaoui , Kathy Barrett , Georgette M. Castanedo , Robert Godemann , Paul A. Mcewan , Xiaolu Wang , Ping Wu , Yamin Zhang , Seth F. Harris , Steven T Staben Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.8b00658 Show Abstract ▼ Abstract: We previously disclosed a series of type I ½ inhibitors of NF-κB inducing kinase (NIK). Inhibition of NIK by these compounds was found to be strongly dependent on the inclusion and absolute stereochemistry of a propargyl tertiary alcohol as it forms critical hydrogen bonds (H-bonds) with NIK. We report that inhibition of protein kinase D1 (PKD1) by this class of compounds is not dependent on H-bond interactions of this tertiary alcohol. This feature was leveraged in the design of highly selective inhibitors of PKD1 that no longer inhibit NIK. A structure-based hypothesis based on the position and flexibility of the α-C-helix of PKD1 vs. NIK is presented.	Jul 2019
I03-Macromolecular Crystallography	Novel fluorescence competition assay for retinoic acid binding proteins Charles W. E. Tomlinson , David R. Chisholm , Roy Valentine , Andrew Whiting , Ehmke Pohl Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.8b00420 Show Abstract ▼ Abstract: Vitamin A derived retinoid compounds have multiple, powerful roles in the cellular growth and development cycle and, as a result, have attracted significant attention from both academic and pharmaceutical research in developing and characterizing synthetic retinoid analogues. Simplifying the hit development workflow for retinoid signaling will improve options available for tackling related pathologies, including tumor growth and neurodegeneration. Here, we present a novel assay that employs an intrinsically fluorescent synthetic retinoid, DC271, which allows direct measurement of the binding of nonlabeled compounds to relevant proteins. The method allows for straightforward initial measurement of binding using existing compound libraries and is followed by calculation of binding constants using a dilution series of plausible hits. The ease of use, high throughput format, and measurement of both qualitative and quantitative binding offer a new direction for retinoid-related pharmacological development.	Nov 2018
	Cystine-based MBioF for maintaining the antioxidant-oxidant balance in airways diseases Marek Wiśniewski , Adam Bieniek , Katarzyna Roszek , Joanna Czarnecka , Paulina Bolibok , Pilar Ferrer , Ivan Da Silva , Artur Piotr Terzyk Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.8b00468 Show Abstract ▼ Abstract: Reactive oxygen species, contributing to oxidant-antioxidant imbalance, initiate damage to the airways cells, inflammatory processes and further pathophysiological effects. Enhancing anti-oxidant properties is the main prophylactic and therapeutic challenge. In this work, a newly synthesized and biocompatible structure of the metal-biomolecule frameworks (MBioF) harnessing cystine as a linker and magnesium as metal nodes, is presented. This structure provides crucial sulfhydryl groups of cysteine, with antioxidant activity, released stepwise in the site of delivery. We prove that once released, the compounds of MBioF increase the intracellular level of cysteine and total antioxidative capability of airways cells. Presented MBioF structures offer new perspectives for clinical applications as therapeutics or preventives maintaining the antioxidant-oxidant balance.	Nov 2018
I04-Macromolecular Crystallography	Potent antimalarial 2-pyrazoyl quinolone bc1 (Qi) inhibitors with improved drug-like properties Weiqian David Hong , Suet C. Leung , Kangsa Amporndanai , Jill Davies , Richard S. Priestley , Gemma Louise Nixon , Neil G. Berry , S. Samar Hasnain , Svetlana Antonyuk , Stephen A. Ward , Giancarlo A. Biagini , Paul O'neill Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.8b00371 Diamond Proposal Number(s): [11740] Show Abstract ▼ Abstract: A series of 2-pyrazolyl quinolones has been designed and synthesized in 5-7 steps to optimize for both in vitro antimalarial potency and various in vitro drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multi-drug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC50 (concentration of drug required to achieve half maximal growth suppression) values in the range of 15 – 33 nM. Furthermore, members of the series retain moderate activity against the atovaquone-resistant parasite isolate (TM90C2B). The described 2-pyrazoyl series displays improved DMPK properties, including improved aqueous solubility compared to previously reported quinolone series and acceptbale safety margin through in vitro cytotocity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Qi site of the parasite bc1 complex, which is supported by crystallographic studies of bovine cytochrome bc1 complex.	Oct 2018
I03-Macromolecular Crystallography	Identification of quinoline-based RIP2 kinase inhibitors with an improved therapeutic index to the hERG ion channel Pamela A. Haile , Linda N. Casillas , Michael J. Bury , John F. Mehlmann , Robert Singhaus , Adam K. Charnley , Terry V. Hughes , Michael P. Demartino , Gren Z. Wang , Joseph J. Romano , Xiaoyang Dong , Nikolay V. Plotnikov , Ami S. Lakdawala , Maire A. Convery , Bartholomew J. Votta , David B. Lipshutz , Biva M. Desai , Barbara Swift , Carol A. Capriotti , Scott B. Berger , Mukesh K. Mahajan , Michael A. Reilly , Elizabeth J. Rivera , Helen H. Sun , Rakesh Nagilla , Carol Lepage , Michael T. Ouellette , Rachel D. Totoritis , Brian T. Donovan , Barry S. Brown , Khuram W. Chaudhary , Peter J. Gough , John Bertin , Robert W. Marquis Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.8b00344 Diamond Proposal Number(s): [1195] Show Abstract ▼ Abstract: RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 μM).	Sep 2018
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Tetrahydroisoquinoline-7-carboxamide Derivatives as New Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors Zhen Wang , Yali Zhang , Sergio G. Bartual , Jinfeng Luo , Tingting Xu , Wenting Du , Qiuju Xun , Zheng-chao Tu , Rolf A Brekken , Xiaomei Ren , Alex N. Bullock , Guang Liang , Xiaoyun Lu , Ke Ding Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.6b00497 Diamond Proposal Number(s): [10619] Show Abstract ▼ Abstract: Acute lung injury (ALI) is a deadly symptom for serious lung inflammation. Discoidin Domain Receptor 1 (DDR1) is a new potential target for anti-inflammatory drug discovery. A new selective tetrahydroisoquinoline-7-carboxamide based DDR1 inhibitor 7ae was discovered to tightly bind the DDR1 protein and potently inhibit its kinase function with a Kd value of 2.2 nM and an IC50 value of 6.6 nM, respectively. The compound dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) release in mouse primary peritoneal macrophages (MPMs). In addition, 7ae also exhibited promising in vivo anti-inflammatory effects in a LPS-induced mouse ALI model. To the best of our knowledge, this is the first “proof of concept” investigation on the potential application of a small molecule DDR1 inhibitor to treat ALI.	Feb 2017
I03-Macromolecular Crystallography	Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors Jeffrey W. Johannes , Stephanie Bates , Carl Beigie , Matthew A. Belmonte , John Breen , Shenggen Cao , Paolo A. Centrella , Matthew A. Clark , John W. Cuozzo , Christoph E. Dumelin , Andrew D. Ferguson , Sevan Habeshian , David Hargreaves , Camil Joubran , Steven Kazmirski , Anthony D. Keefe , Michelle L. Lamb , Haiye Lan , Yunxia Li , Hao Ma , Scott Mlynarski , Martin J. Packer , Philip B. Rawlins , Daniel W. Robbins , Haidong Shen , Eric A. Sigel , Holly H. Soutter , Nancy Su , Dawn M. Troast , Haiyun Wang , Kate F. Wickson , Chengyan Wu , Ying Zhang , Qiuying Zhao , Xiaolan Zheng , Alexander W. Hird Acs Medicinal Chemistry Letters 8, 239 - 244 DOI: 10.1021/acsmedchemlett.6b00464 Show Abstract ▼ Abstract: Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein–ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4–11 cells with an IC50 of 3 μM after 6 h.	Feb 2017

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