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Development of dihydropyrrolopyridinone-based PKN2/PRK2 chemical tools to enable drug discovery

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. and Ward, Simon E. ORCID: 2022. Development of dihydropyrrolopyridinone-based PKN2/PRK2 chemical tools to enable drug discovery. Bioorganic and Medicinal Chemistry Letters 60 , 128588. 10.1016/j.bmcl.2022.128588

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Publisher: Elsevier
ISSN: 0960-894X
Date of First Compliant Deposit: 26 April 2022
Date of Acceptance: 22 January 2022
Last Modified: 18 May 2023 00:10

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