Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton’s Tyrosine Kinase

Although
Bruton’s tyrosine kinase (BTK) has been recognized
as a validated drug target for the treatment of B-cell malignances,
the emergence of clinical resistance to the first-generation covalent
BTK inhibitors is becoming a serious concern. As a part of our effort
to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines
was identified as noncovalent inhibitors of both the wild-type and
C481S mutant BTKs. Subsequent lead optimization led to the identification
of an orally available, potent, and selective BTK inhibitor 13f (AS-1763) as a next-generation noncovalent BTK inhibitor.
With significant efficacies in vivo tumor xenograft models, AS-1763
has advanced to phase 1 clinical trials.