Exploration of tricyclic heterocycles as core structures for RIOK2 inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Right open reading frame kinase 2 (RIOK2) is an atypical kinase implicated in various cancers like NSCLC, AML, and glioblastoma.
• The precise biological functions of RIOK2 are not fully understood, necessitating the development of specific inhibitors.
• RIOK2 inhibitors serve as crucial research tools and potential therapeutic agents for cancer treatment.

Purpose of the Study:

• To investigate the structure-activity relationships of RIOK2 inhibitors.
• To confirm the significance of the "V-shaped" structure in the previously identified inhibitor CQ211 for RIOK2 binding.
• To design and synthesize novel tricyclic compounds with varied core structures to evaluate their binding affinity to RIOK2.

Main Methods:

• Design and synthesis of diverse tricyclic heterocycles.
• Modification of the core structure of the known RIOK2 inhibitor CQ211.
• Evaluation of the binding affinities of synthesized compounds with RIOK2.

Main Results:

• A series of tricyclic compounds with alternative core structures were successfully synthesized.
• The binding affinities of these novel heterocycles to RIOK2 were quantitatively assessed.
• The study provides insights into the structural requirements for potent RIOK2 inhibition.

Conclusions:

• The research elucidates the importance of specific structural features for RIOK2 inhibition.
• The findings contribute to the development of more effective RIOK2 inhibitors for cancer research and therapy.
• Further studies can build upon these results to explore RIOK2's role in disease.