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

Abstract

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.

N-Acyl-5,5-dimethylhydantoin, a New Mild Acyl-Transfer Reagent in Pd Catalysis: Highly Efficient Synthesis of Functionalized Ketones

“…Carbon–nitrogen bonds widely exist in chemistry, biology, and natural pharmaceutical molecules . In recent decades, tremendous progress has been reported in the development of transition-metal-catalyzed C–N bond formation approaches for the synthesis of oxazoles, quinolines, and N -based heterocycles .…”

Identification of CHK1 Kinase Inhibitors Using Structure-Based Pharmacophore Modeling and Molecular Docking

“…Finally, the crystal structures for CHK1 in complex with ligands whose IC 50s were less than 10 nM, unmutated and with a resolution better than 2.5 Å were considered. The considered crystal structures have PDB codes of 2E9N [31] , 2YDK [26] , 3OT8 [12] and 6FCF [32] . Out of those, only the 3OT8 crystal complex generated successful queries.…”

The identification and application of a robust ω-transaminase with high tolerance towards substrates and isopropylamine from a directed soil metagenome

“…To experimentally explore the industrial potential of recombinant ω-TAs for asymmetric amination, the prochiral ketone 1-Boc-3-piperidone (2t), whose corresponding chiral amine is a common motif found in a variety of pharmaceuticals [32][33][34] (Scheme 1), was selected as the amine acceptor. Meanwhile, the industrially favored IPA was chosen as the amine donor.…”