1 research outputs found
Discovery of a Series of 2,5-Diaminopyrimidine Covalent Irreversible Inhibitors of Bruton’s Tyrosine Kinase with in Vivo Antitumor Activity
Bruton’s tyrosine kinase (Btk)
is an attractive drug target for treating several B-cell lineage cancers.
Ibrutinib is a first-in-class covalent irreversible Btk inhibitor
and has demonstrated impressive effects in multiple clinical trials.
Herein, we present a series of novel 2,5-diaminopyrimidine covalent
irreversible inhibitors of Btk. Compared with ibrutinib, these inhibitors
exhibited a different selectivity profile for the analyzed kinases
as well as a dual-action mode of inhibition of both Btk activation
and catalytic activity, which counteracts a negative regulation loop
for Btk. Two compounds from this series, <b>31</b> and <b>38</b>, showed potent antiproliferative activities toward multiple
B-cell lymphoma cell lines, including germinal center B-cell-like
diffuse large B cell lymphoma (GCB-DLBCL) cells. In addition, compound <b>31</b> significantly prevented tumor growth in a mouse xenograft
model