- Discovery of Novel UDP- N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa
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This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.
- Andersen, Ole A.,Barbeau, Olivier R.,Barker, John,Cain, Ricky,Centrella, Paolo A.,Clark, Matthew A.,Compper, Christel,Corbett, David,Cuozzo, John W.,Dejob, Magali,Dejonge, Boudewijn L. M.,Deng, Boer,Dickie, Anthony P.,Dorali, Alain,Etheridge, Donnya,Evans, Sian,Faulkner, Adele,Gadouleau, Elise,Gorman, Timothy,Haase, Denes,Holbrow-Wilshaw, Maisie,Hunt, Avery,Keefe, Anthony D.,Krulle, Thomas,Li, Xianfu,Lumley, Christopher,Mertins, Barbara,Napier, Spencer,Odedra, Rajesh,Papadopoulos, Kostas,Parkes, Alastair L.,Roumpelakis, Vasileios,Ryan, M. Dominic,Sanzone, Angelo,Sigel, Eric A.,Southey, Michelle,Soutter, Holly T.,Spear, Kate,Stein, Daniel B.,Thommes, Pia,Trimby, Emily,Troast, Dawn M.,Williams, Jennifer,Zahn, Michael,Zhang, Ying
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p. 14377 - 14425
(2021/10/25)
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- IMMUNE EFFECTOR CELL THERAPIES WITH ENHANCED EFFICACY
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Provided herein is the use of LSD1 inhibitors in connection with use and manufacture of immune effector cells (e.g., T cells, NK cells), e.g., engineered to express a chimeric antigen receptor (CAR), to treat a subject having a disease, e.g., a disease associated with expression of a tumor antigen.
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Page/Page column 291
(2018/04/17)
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- IMMUNE EFFECTOR CELL THERAPIES WITH ENHANCED EFFICACY
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Provided are the use of LSD1 inhibitors in connection with use and manufacture of immune effector cells (e.g., T cells, NK cells), e.g., engineered to express a chimeric antigen receptor (CAR), to treat a subject having a disease, e.g., a disease associated with expression of a tumor antigen.
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Page/Page column 337
(2017/07/31)
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- Process for producing optically active carbinols
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The present invention relates to a process for producing optically active halomethyl phenyl carbinols of the formula (1), comprising reducing halomethyl phenyl ketones of the formula (2) using an asymmetric reducing agent obtained from boranes and optically active α-phenyl-substituted-β-amino alcohols of the formula (3) or optically active α-non-substituted-β-amino alcohols of the formula (4). The present invention further relates to a process for producing optically active carbinols, comprising reacting a prochiral keytone with an asymmetric reducing agent obtained from optically active β-amino alcohols of the formula (5), a metal boron hydride and Lewis acid or lower dialkyl sulfuric acid. All of the formulas (1) to (5) are the same as shown in the specification.
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- Synteza zwiazkow o potencjalnym dzialaniu radiouczulajacym. VII. Synteza alkiloksantogenianow 3-bromo-4-chlorofenacylowych
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In the frame-work of search for new potential radiosensitizers a series novel 3-bromo-4-chlorophenacyl alkylxanthates were synthesized by reacting 3-bromo-4-chlorophenacyl bromide with potassium alkylxanthates, in which allyl, ethyl, propyl, isopropyl, bu
- Skwarski, Dionizy,Sobolewski, Henryk
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