Recent developments around inhibitors of the 90 kDa ribosomal S6 serine/threonine kinases (RSK1-4) have been focused on the optimization of known pan-RSK inhibitors such as SL0101 and BI-D1870. The RSKs are an intriguing target for cancer therapy due to their role as downstream effectors in the MAPK pathway. Herein, we focus on the utilization of computational modeling in inhibitor screening and development for RSK, and we examine computational artifacts in molecular modeling, quantum mechanical calculations, molecular dynamics, and high throughput screening. Variation between RSK structural models is also evident, given the available crystal structures, and liberties in homology modeling and dynamic conformations may capture new targeting approaches for these proteins. Furthermore, pan-kinase inhibitors are often used to target RSK since the four different RSK isoforms share a high degree of homology; however, they have distinct biological actions in cancer. A majority of RSK modeling generalizes the conclusions from one isoform onto the others; therefore, forming accurate isoform specific models containing their subtle differences will be key to the development of isoform-selective inhibitors. This review consolidates existing RSK models and the isoform specific structural differences that have and have not been considered, evaluates inhibition studies that have started to build upon RSK selectivity, including for its isoforms, and assesses other inhibitory binding sites to offer potential pathways forward. The leveraging of these differences through computational methods aims to guide next-generation isoform-selective RSK inhibitors.

2025-01-01·Anti-Cancer Agents in Medicinal Chemistry

Targeting RSK2 in Cancer Therapy: A Review of Natural Products

Review

作者: Wu, Xinyan ; Wu, Tianhui ; Wang, Zhaobo ; Guo, Weiqiang ; Liu, Xin ; Chen, Ziming

P90 ribosomal S6 kinase 2 (RSK2) is an important member of the RSK family, functioning as a kinase enzyme that targets serine and threonine residues and contributes to regulating cell growth. RSK2 comprises two major functional domains: the N-terminal kinase domain (NTKD) and the C-terminal kinase domain (CTKD). RSK2 is situated at the lower end of the Mitogen-activated protein kinases (MAPK) signaling pathway and is phosphorylated by the direct regulation of Extracellular signal-regulating kinase (ERK). RSK2 has been found to play a pivotal role in regulating cell proliferation, apoptosis, metastasis, and invasion in various cancer cells, including breast cancer and melanoma. Consequently, RSK2 has emerged as a potential target for the development of anti-cancer drugs. Presently, several inhibitors are undergoing clinical trials, such as SL0101. Current inhibitors of RSK2 mainly bind to its NTK or CTK domains and inhibit their activity. Natural products serve as an important resource for drug development and screening and with the potential to identify RSK2 inhibitors. This article discusses how RSK2 influences tumor cell proliferation, prevents apoptosis, arrests the cell cycle process, and promotes cancer metastasis through its regulation of downstream pathways or interaction with other biological molecules. Additionally, the paper also covers recent research progress on RSK2 inhibitors and the mechanisms of action of natural RSK2 inhibitors on tumors. This review emphasizes the significance of RSK2 as a potential therapeutic target in cancer and offers a theoretical basis for the clinical application of RSK2 inhibitors.

2024-10-01·NEUROSCIENCE

Ribosomal S6 kinase signaling regulates neuronal viability during development and confers resistance to excitotoxic cell death in mature neurons

Article

作者: Karelina, Kate ; Horning, Paul ; Georgette Ang, Pia ; Obrietan, Karl ; Hoyt, Kari R

The Ribosomal S6 Kinase (RSK) family of serine/threonine kinases function as key downstream effectors of the MAPK signaling cascade. In the nervous system, RSK signaling plays crucial roles in neuronal development and contributes to activity-dependent neuronal plasticity. This study examined the role of RSK signaling in cell viability during neuronal development and in neuroprotection in the mature nervous system. Using neuronal cell-culture-based profiling, we found that suppressing RSK signaling led to significant cell death in developing primary neuronal cultures. To this end, treatment with the RSK inhibitors BiD1870 or SL0101 on the first day of culturing resulted in over 80% cell death. In contrast, more mature cultures showed attenuated cell death upon RSK inhibition. Inhibition of RSK signaling during early neuronal development also disrupted neurite outgrowth and cell growth. In maturing hippocampal explant cultures, treatment with BiD1870 had minimal effects on cell viability, but led to a striking augmentation of NMDA-induced cell death. Finally, we used the endothelin 1 (ET-1) model of ischemia to examine the neuroprotective effects of RSK signaling in the mature hippocampus in vivo. Notably, in the absence of RSK inhibition, the granule cell layer (GCL) was resistant to the effects of ET-1; However, disruption of RSK signaling (via the microinjection of BiD1870) prior to ET-1 injection triggered cell death within the GCL, thus indicating a neuroprotective role for RSK signaling in the mature nervous system. Together these data reveal distinct, developmentally-defined, roles for RSK signaling in the nervous system.

100 项与 SL0101 相关的药物交易

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