Design and Optimization of Novel Benzimidazole- and Imidazo[4,5‑b]pyridine-Based ATM Kinase Inhibitors with Subnanomolar Activities
The ATM kinase is a promising target in cancer treatment as an important regulator of the cellular response to DNA double-strand breaks. In this work, we present a new class of specific benzimidazole-based ATM inhibitors with picomolar potency against the isolated enzyme and favorable selectivity wi...
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| Veröffentlicht in: | Journal of medicinal chemistry 2023-06, Vol.66 (11), p.7304-7330 |
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| container_title | Journal of medicinal chemistry |
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| creator | Dimitrov, Teodor Moschopoulou, Athina Anastasia Seidel, Lennart Kronenberger, Thales Kudolo, Mark Poso, Antti Geibel, Christian Wölffing, Pascal Dauch, Daniel Zender, Lars Schollmeyer, Dieter Bajorath, Jürgen Forster, Michael Laufer, Stefan |
| description | The ATM kinase is a promising target in cancer treatment as an important regulator of the cellular response to DNA double-strand breaks. In this work, we present a new class of specific benzimidazole-based ATM inhibitors with picomolar potency against the isolated enzyme and favorable selectivity within relative PIKK and PI3K kinases. We could identify two promising inhibitor subgroups with significantly different physicochemical properties, which we developed simultaneously. These efforts lead to numerous highly active inhibitors with picomolar enzymatic activities. Furthermore, initial low cellular activities on A549 cells could be increased significantly in numerous examples resulting in cellular IC50 values in the subnanomolar range. Further characterization of the highly potent inhibitors 90 und 93 revealed promising pharmacokinetic properties and strong activities in organoids in combination with etoposide. Additionally, 93 showed no off-target activities within a kinome-representative mini kinase panel, with favorable selectivities within the PIKK- and PI3K-families. |
| doi_str_mv | 10.1021/acs.jmedchem.2c02104 |
| format | Article |
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In this work, we present a new class of specific benzimidazole-based ATM inhibitors with picomolar potency against the isolated enzyme and favorable selectivity within relative PIKK and PI3K kinases. We could identify two promising inhibitor subgroups with significantly different physicochemical properties, which we developed simultaneously. These efforts lead to numerous highly active inhibitors with picomolar enzymatic activities. Furthermore, initial low cellular activities on A549 cells could be increased significantly in numerous examples resulting in cellular IC50 values in the subnanomolar range. Further characterization of the highly potent inhibitors 90 und 93 revealed promising pharmacokinetic properties and strong activities in organoids in combination with etoposide. 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| ispartof | Journal of medicinal chemistry, 2023-06, Vol.66 (11), p.7304-7330 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Ataxia Telangiectasia Mutated Proteins Benzimidazoles - pharmacology Etoposide Humans Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide-3 Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyridines - pharmacology |
| title | Design and Optimization of Novel Benzimidazole- and Imidazo[4,5‑b]pyridine-Based ATM Kinase Inhibitors with Subnanomolar Activities |
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