Optimization of novel reversible Bruton's tyrosine kinase inhibitors identified using Tethering-fragment-based screens. Issue 13 (1st July 2019)

• Record Type: Journal Article
• Authors: Hopkins, Brian T.; Bame, Eris; Bell, Noah; Bohnert, Tonika; Bowden-Verhoek, Jon K.; Bui, Minna; Cancilla, Mark T.; Conlon, Patrick; Cullen, Patrick; Erlanson, Daniel A.; Fan, Junfa; Fuchs-Knotts, Tarra; Hansen, Stig; Heumann, Stacey; Jenkins, Tracy J.; Marcotte, Douglas; McDowell, Bob; Mertsching, Elisabeth; Negrou, Ella; Otipoby, Kevin L.; Poreci, Urjana; Romanowski, Michael J.; Scott, Daniel; Silvian, Laura; Yang, Wenjin; Zhong, Min
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 13(2019)
• Page Start: 2905
• Page End: 2913
• Publication Date: 2019-07-01
• Subjects: Bruton's Tyrosine Kinase (BTK) -- Fragment screen -- Computer aid drug design (CADD); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.05.021
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Since the approval of ibrutinib for the treatment of B-cell malignancies in 2012, numerous clinical trials have been reported using covalent inhibitors to target Bruton's tyrosine kinase (BTK) for oncology indications. However, a formidable challenge for the pharmaceutical industry has been the identification of reversible, selective, potent molecules for inhibition of BTK. Herein, we report application of Tethering-fragment-based screens to identify low molecular weight fragments which were further optimized to improve on-target potency and ADME properties leading to the discovery of reversible, selective, potent BTK inhibitors suitable for pre-clinical proof-of-concept studies.