Stereoselective Covalent Targeting of BTK(C481S) and Kinases with β-Lactone Electrophiles

Abstract

The cysteine to serine mutation at residue 481 of Brutons tyrosine kinase (BTK) is the most common mechanism of clinical resistance against ibrutinib for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. We report small molecule ligands containing chiral {beta}-lactone electrophiles to address this challenge. The asymmetric warhead enabled stereoselective covalent modification of wild-type and ibrutinib-resistant mutant BTK(C481S) through distinct sites of reactivity. Building on these findings, we developed kinase-directed {beta}-lactone probes and demonstrated that individual enantiomers preferentially engage distinct subsets of the kinome. These studies establish {beta}-lactones as stereochemically encodable covalent warheads whose stereochemistry can serve as a selectivity filter in covalent drug discovery. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/736436v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1b407c6org.highwire.dtl.DTLVardef@6a79ddorg.highwire.dtl.DTLVardef@66a59dorg.highwire.dtl.DTLVardef@102ecc7_HPS_FORMAT_FIGEXP M_FIG C_FIG