Sussex Drug Discovery Centre, University of Sussex, Sussex House, Falmer, Brighton BN1 9RH, United Kingdom.
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.
Bioorg Med Chem Lett. 2022 Mar 15;60:128588. doi: 10.1016/j.bmcl.2022.128588. Epub 2022 Jan 29.
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 K = 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.
蛋白激酶 N 蛋白（PKN1、PKN2 和 PKN3）是 Rho GTPase 的效应物。它们参与了多种生物学过程，如细胞骨架组织、细胞迁移、黏附和细胞周期。最近，PKN 被报道对包括前列腺癌和乳腺癌在内的几种肿瘤细胞系的生存至关重要。在这里，我们报告了基于二氢吡啶并吡啶酮的 PKN2 及其最接近的同源物 PKN1 的抑制剂的开发，以及它们的相关结构-活性关系（SAR）。我们的研究确定了一系列具有高活性的分子，其中化合物 8 对 PKN2 的 K i 值为 8 nM，对 PKN1 的选择性为 14 倍。通过 NanoBRET 细胞测定评估了 PKN2 的膜通透性和靶标结合。重要的是，在更广泛的人类激酶组和其他激酶家族成员中实现了良好的选择性。这些化合物为 PKN1/2 开发化合物的先导优化提供了有力的起点。
