2. Academic Validation
  3. Development of dihydropyrrolopyridinone-based PKN2/PRK2 chemical tools to enable drug discovery

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

  • Bioorg Med Chem Lett. 2022 Mar 15;60:128588. doi: 10.1016/j.bmcl.2022.128588.
Fiona Scott 1,  Angela M Fala 2,  Jessica E Takarada 2,  Mihaela P Ficu 1,  Lewis E Pennicott 1,  Tristan D Reuillon 1,  Rafael M Couñago 2,  Katlin B Massirer 3,  Jonathan M Elkins 4,  Simon E Ward 5
Affiliations

Affiliations

  • 1 Sussex Drug Discovery Centre, University of Sussex, Sussex House, Falmer, Brighton BN1 9RH, United Kingdom.
  • 2 Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil; Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil.
  • 3 Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil; Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil. Electronic address: [email protected].
  • 4 Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil; Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom. Electronic address: [email protected].
  • 5 Medicines Discovery Institute, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom. Electronic address: [email protected].
PMID: 35104640 DOI: 10.1016/j.bmcl.2022.128588
Abstract

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.

Keywords

Chemical tools; Dihydropyrrolopyridinone; Kinase inhibitors; PKN1; PKN2; PRK2.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145899
    98.48%, PKN2 Inhibitor