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Your search keyword '"Dowling, James E."' showing total 2 results
Start Over Author "Dowling, James E." Topic protein-tyrosine kinases
2 results on '"Dowling, James E."'

1. Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors.

Author

Grimster NP, Gingipalli L, Balazs A, Barlaam B, Boiko S, Boyd S, Dry H, Goldberg FW, Ikeda T, Johnson T, Kawatkar S, Kemmitt P, Lamont S, Lorthioir O, Mfuh A, Patel J, Pike A, Read J, Romero R, Sarkar U, Sha L, Simpson I, Song K, Su Q, Wang H, Watson D, Wu A, Zehnder TE, Zheng X, Li S, Dong Z, Yang D, Song Y, Wang P, Liu X, Dowling JE, and Edmondson SD

Subjects
Syk Kinase, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases, Signal Transduction
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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Published
2023
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2. Identification of a novel series of azabenzimidazole-derived inhibitors of spleen tyrosine kinase.

Author

Kawatkar, Sameer P., Barlaam, Bernard, Kemmitt, Paul, Simpson, Iain, Watson, David, Wang, Peng, Lamont, Scott, Su, Qibin, Boiko, Scott, Ikeda, Timothy, Patel, Joe, Pike, Andy, Pollard, Hannah, Read, Jon, Sarkar, Ujjal, Wang, Haiyun, Wen, Quanshan, Yan, Zhiyuan, Dowling, James E., and Dry, Hannah

Subjects
*PROTEIN-tyrosine kinases, *SPLEEN, *DATA mining, *AUTOIMMUNE diseases, *CELL growth
Abstract

Spleen Tyrosine Kinase (SYK) is a well-studied enzyme with therapeutic applications in oncology and autoimmune diseases. We identified an azabenzimidazole (ABI) series of SYK inhibitors by mining activity data of 86,000 compounds from legacy biochemical assays with SYK and other homologous kinases as target enzymes. A structure-based design and hybridization approach was then used to improve the potency and kinase selectivity of the hits. Lead compound 23 from this novel ABI series has a SYK IC 50 = 0.21 nM in a biochemical assay and inhibits growth of SUDHL-4 cells at a GI 50 = 210 nM. [ABSTRACT FROM AUTHOR]

Published
2020
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