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3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6
Affiliation:1. Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA;2. Department of Cancer Research, Merck Research Laboratories, West Point, PA 19486, USA;3. Department of Structural Biology, Merck Research Laboratories, West Point, PA 19486, USA;4. Department of Molecular Systems, Merck Research Laboratories, West Point, PA 19486, USA;1. CHEMSOL, 1 Harcourt Road, Aberdeen AB15 5NY, United Kingdom;2. Department of Chemistry, University of Aberdeen, Old Aberdeen, AB 24 3UE, United Kingdom;1. Health Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India;2. Manipal Centre for Natural Sciences, Manipal University, Manipal 576104, India;1. School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia;2. Brain and Mind Research Institute, Sydney, NSW 2050, Australia;3. Discipline of Medical Radiation Sciences, The University of Sydney, Sydney, NSW 2006, Australia
Abstract:The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC50 = 0.30 nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.
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