TY - JOUR
T1 - Adventures in Scaffold Morphing
T2 - Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors
AU - Yang, Bin
AU - Vasbinder, Melissa M.
AU - Hird, Alexander W.
AU - Su, Qibin
AU - Wang, Haixia
AU - Yu, Yan
AU - Toader, Dorin
AU - Lyne, Paul D.
AU - Read, Jon A.
AU - Breed, Jason
AU - Ioannidis, Stephanos
AU - Deng, Chun
AU - Grondine, Michael
AU - Degrace, Nancy
AU - Whitston, David
AU - Brassil, Patrick
AU - Janetka, James W.
PY - 2018/2/8
Y1 - 2018/2/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85041895280
U2 - 10.1021/acs.jmedchem.7b01490
DO - 10.1021/acs.jmedchem.7b01490
M3 - Article
C2 - 29301085
AN - SCOPUS:85041895280
SN - 0022-2623
VL - 61
SP - 1061
EP - 1073
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -