Development of dihydropyrrolopyridinone-based PKN2/PRK2 chemical tools to enable drug discovery
| Autor: | Scott, Fiona, Fala, Angela M., Takarada, Jessica E., Ficu, Mihaela P., Pennicott, Lewis E., Reuillon, Tristan D., Couñago, Rafael M., Massirer, Katlin B., Elkins, Jonathan M., Ward, Simon E. |
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| Rok vydání: | 2021 |
| Předmět: |
Dose-Response Relationship
Drug Molecular Structure Cell Survival Pyridones Organic Chemistry Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Biochemistry Molecular Docking Simulation Structure-Activity Relationship Drug Development Drug Discovery Molecular Medicine Humans Pyrroles Drug Screening Assays Antitumor Molecular Biology Protein Kinase Inhibitors Protein Kinase C Cell Proliferation HeLa Cells |
| Zdroj: | Bioorganicmedicinal chemistry letters. 60 |
| ISSN: | 1464-3405 0960-894X |
| Popis: | The Protein Kinase N proteins (PKN1, PKN2 and PKN3) are Rho GTPase effectors. They are involved in several biological processes such as cytoskeleton organization, cell mobility, adhesion, and cell cycle. Recently PKNs have been reported as essential for survival in several tumor cell lines, including prostate and breast cancer. Here, we report the development of dihydropyrrolopyridinone-based inhibitors for PKN2 and its closest homologue, PKN1, and their associated structure–activity relationship (SAR). Our studies identified a range of molecules with high potency exemplified by compound 8 with Ki = 8 nM for PKN2 and 14x selectivity over PKN1. Membrane permeability and target engagement for PKN2 were assessed by a NanoBRET cellular assay. Importantly, good selectivity across the wider human kinome and other kinase family members was achieved. These compounds provide strong starting points for lead optimization to PKN1/2 development compounds. |
| Databáze: | OpenAIRE |
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