Acrylamide Bioisosterism: Alkenyl Aromatic Heterocycles as Reactivity-Tunable Warheads for Covalent BTK Inhibitors

Cysteine-targeted covalent inhibitors have traditionally
used a
few electrophilic warheads, with Michael acceptors being the most
common. However, their stability and selectivity in physiological
conditions require enhancement. Inspired by the principles of bioisosterism,
we have developed an innovative class of tunable electrophilic warheads
by substituting the conventional acrylamide moiety in covalent inhibitors
with alkenyl aromatic heterocycles. This approach aimed to enhance
selectivity and reactivity. We synthesized a library of these warheads
and integrated them into the BTK inhibitor ibrutinib. The resulting
compounds showed strong and selective BTK inhibition, effectively
blocking B-cell receptor signaling and cancer cell growth. Key derivatives
specifically bound to the Cys481 residue of BTK, as confirmed by mass
spectrometry and cellular tests. A lead compound demonstrated good
pharmacokinetics and significant antitumor effects in a mouse model,
highlighting this bioisosteric strategy as a promising avenue for
covalent drug development.