- Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors
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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.
- Yang, Bin,Vasbinder, Melissa M.,Hird, Alexander W.,Su, Qibin,Wang, Haixia,Yu, Yan,Toader, Dorin,Lyne, Paul D.,Read, Jon A.,Breed, Jason,Ioannidis, Stephanos,Deng, Chun,Grondine, Michael,Degrace, Nancy,Whitston, David,Brassil, Patrick,Janetka, James W.
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p. 1061 - 1073
(2018/02/17)
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- BICYCLIC PYRIDAZINE COMPOUNDS AS PIM INHIBITORS
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The invention relates to bicyclic compounds of formulas I and I', and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.
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Page/Page column 102
(2012/11/13)
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- HETEROCYCLIC TYROSINE KINASE INHIBITORS
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The present invention provides compounds useful as inhibitors of Tec family kinases, compositions thereof, and methods of using the same. In certain embodiments, the present invention provides pharmaceutical formulations comprising provided compounds. In certain embodiments, the present invention provides a method of decreasing enzymatic activity of a Tec kinase family member. In some embodiments, such methods include contacting a Tec kinase family member with an effective amount of a Tec kinase family member inhibitor. In certain embodiments, the present invention provides a method of treating a disorder responsive to Tec kinase family inhibition in a subject in need thereof.
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Page/Page column 168
(2012/05/19)
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