Triazine-Based Covalent DNA-Encoded Libraries for Discovery of Covalent Inhibitors of Target Proteins

Since ibrutinib was approved by the FDA as an effective
monotherapy
for chronic lymphocytic leukemia (CLL) and multilymphoma, more and
more FDA-approved covalent drugs are coming back into the market.
On this occasion, the resurgence of interest in covalent drugs calls
for more hit discovery techniques. However, the limited numbers of
covalent libraries prevent the development of this area. Herein, we
report the design of covalent DNA-encoded library (DEL) and its selection
method for the discovery of covalent inhibitors for target proteins.
These triazine-based covalent DELs yielded potent compounds after
covalent selection against target proteins, including Bruton’s
Tyrosine Kinase (BTK), Janus kinase 3 (JAK3), and peptidyl-prolyl
cis/trans isomerase NIMA-interacting-1 (Pin1).