Related Experiment Video
Updated: Aug 6, 2026

Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
Published on: February 28, 2025
Stereoselective Covalent Targeting of BTK(C481S) and Kinases with β-Lactone Electrophiles
Celine D Wang1,2, Polina E Barzova1, Julian Robles1
1Department of Chemistry, University of California, Berkeley, California 94720, USA.
None:
The cysteine to serine mutation at residue 481 of Bruton's 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 β-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 β-lactone probes and demonstrated that individual enantiomers preferentially engage distinct subsets of the kinome. These studies establish β-lactones as stereochemically encodable covalent warheads whose stereochemistry can serve as a selectivity filter in covalent drug discovery.
Related Concept Videos
α-Alkylation of Ketones via Enolate Ions
Targeted Cancer Therapies
There are several types of targeted therapies against specific...
Regioselectivity and Stereochemistry of Hydroboration
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.
SN2 Reaction: Stereochemistry
If the substrate is an achiral molecule at the α-carbon, the inversion of configuration is not observed.
Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
Alkylation of β-Ketoester Enolates: Acetoacetic Ester Synthesis

