Indole RSK inhibitors. Part 1: discovery and initial SAR.

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Drug Discovery

Background:

• The 90 kDa ribosomal S6 kinase (RSK) is a key signaling enzyme implicated in various cellular processes.
• Developing specific inhibitors for RSK is crucial for understanding its role in disease and for therapeutic intervention.
• A novel chemical scaffold, 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide, was explored for RSK inhibition.

Purpose of the Study:

• To identify and characterize novel inhibitors of the 90 kDa ribosomal S6 kinase (RSK).
• To define the pharmacophore of a new series of RSK inhibitors based on a diazepinoindole scaffold.
• To establish a basis for further optimization towards selective kinase inhibitors.

Main Methods:

• High-throughput screening (HTS) was employed to discover initial inhibitor candidates.
• X-ray crystallography of RSK provided structural insights for pharmacophore elucidation.
• Exploratory structure-activity relationship (SAR) studies guided the optimization process.

Main Results:

• A series of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide derivatives were identified as RSK inhibitors.
• Key structural features defining the RSK inhibitor pharmacophore were determined.
• Several compounds, including analogs 43, 44, and 55, demonstrated significant cell potency.

Conclusions:

• The identified scaffold is a promising starting point for the development of potent RSK inhibitors.
• The potent compounds serve as valuable leads for future medicinal chemistry efforts focused on kinase selectivity.
• This work contributes to the ongoing search for targeted therapies involving RSK signaling pathways.