Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window
| Autor: | Jennifer Epler, Joachim Rudolph, Joy Drobnick, Roxanne Vega, Ignacio Aliagas, Sreemathy Ramaswamy, Elizabeth Blackwood, Klaus P. Hoeflich, Diana Jakubiak, Wendy Lee, Haiming Zhang, Xianrui Zhao, Weiru Wang, Christopher E. Heise, David Favor, Chudi Ndubaku, Thomas W. O'Brien, Gary A. Cain, Lesley J. Murray, Paroma Chakravarty, Hank La, Christy C. Ong, Ping Dong, Connie Chan, James J. Crawford, Angela Oh, Yu Zhong, Dolores Díaz, Lewis J. Gazzard |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug Pyridines Pyridones media_common.quotation_subject Pharmacology 03 medical and health sciences Mice Structure-Activity Relationship PAK1 Drug Discovery Structure–activity relationship Animals p21-activated kinases Protein Kinase Inhibitors media_common Mice Inbred BALB C Dose-Response Relationship Drug Molecular Structure Kinase Chemistry Acute toxicity 030104 developmental biology Pyrimidines p21-Activated Kinases Cardiovascular Diseases Toxicity Acute Disease Molecular Medicine Female Animal studies |
| Zdroj: | Journal of medicinal chemistry. 59(11) |
| ISSN: | 1520-4804 |
| Popis: | p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window. To attempt mitigating the toxicity, we introduced significant structural changes, culminating in the discovery of the potent pyridone side chain analogue G-9791. Mouse tolerability studies with this compound, other members of this series, and compounds from two structurally distinct classes revealed persistent toxicity and a correlation of minimum toxic concentrations and PAK1/2 mediated cellular potencies. Broad screening of selected PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets. Our data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition, and cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery. |
| Databáze: | OpenAIRE |
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