Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors

Checkpoint
kinase 1 (CHK1) inhibitors are potential cancer therapeutics
that can be utilized for enhancing the efficacy of DNA damaging agents.
Multiple small molecule CHK1 inhibitors from different chemical scaffolds
have been developed and evaluated in clinical trials in combination
with chemotherapeutics and radiation treatment. Scaffold morphing
of thiophene carboxamide ureas (TCUs), such as AZD7762 (1) and a related series of triazoloquinolines (TZQs), led to the identification
of fused-ring bicyclic CHK1 inhibitors, 7-carboxamide thienopyridines
(7-CTPs), and 7-carboxamide indoles. X-ray crystal structures reveal
a key intramolecular noncovalent sulfur–oxygen interaction
in aligning the hinge-binding carboxamide group to the thienopyridine
core in a coplanar fashion. An intramolecular hydrogen bond to an
indole NH was also effective in locking the carboxamide in the preferred
bound conformation to CHK1. Optimization on the 7-CTP series resulted
in the identification of lead compound 44, which displayed
respectable drug-like properties and good in vitro and in vivo
potency.