Molecular Bidents with Two Electrophilic Warheads as a New Pharmacological Modality

A systematic strategy
to develop dual-warhead inhibitors
is introduced
to circumvent the limitations of conventional covalent inhibitors
such as vulnerability to mutations of the corresponding nucleophilic
residue. Currently, all FDA-approved covalent small molecules feature
one electrophile, leaving open a facile route to acquired resistance.
We conducted a systematic analysis of human proteins in the protein
data bank to reveal ∼400 unique targets amendable to dual covalent
inhibitors, which we term “molecular bidents”. We demonstrated
this strategy by targeting two kinases: MKK7 and EGFR. The designed
compounds, ZNL-8162 and ZNL-0056, are ATP-competitive inhibitors that
form two covalent bonds with cysteines and retain potency against
single cysteine mutants. Therefore, molecular bidents represent a
new pharmacological modality with the potential for improved selectivity,
potency, and drug resistance profile.