Development of a SIN1 Targeting Inhibitor as a Novel Therapeutic Approach for the Treatment of Malignancies

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The mechanistic target of rapamycin (mTOR) pathway is crucial in tumorigenesis.
• Existing catalytic mTOR inhibitors face resistance due to feedback loops.
• Selective mTORC2 inhibitors are needed to overcome resistance and improve anti-tumor effects.

Purpose of the Study:

• To identify and develop novel selective mTORC2 inhibitors.
• To investigate the anti-tumor potential of SIN1 inhibitors.
• To evaluate SIN1 inhibition in combination with existing anti-neoplastic agents.

Main Methods:

• In-silico screening and medicinal chemistry optimization to identify SIN1 binders.
• Assessment of SIN1 inhibitor effects on post-translational modifications and protein-protein interactions.
• Evaluation of signaling pathway inhibition (mTORC2, RS mTORC1, RAS/MAPK) and cell proliferation in cancer cell lines.

Main Results:

• Identification of small molecules targeting the unique mTORC2 component, SIN1.
• Demonstration that SIN1 inhibition alters signaling pathways and blocks mTORC2/RS mTORC1 activity.
• Inhibition of wildtype RAS activation, downstream MAPK signaling, and cancer cell proliferation.
• Enhanced efficacy of FDA-approved anti-neoplastic agents in vitro.

Conclusions:

• SIN1 inhibitors represent a novel class of targeted cancer therapeutics.
• Targeting SIN1 can effectively block oncogenic signaling and inhibit tumor growth.
• SIN1 inhibition may overcome resistance mechanisms associated with current mTOR inhibitors and enhance combination therapies.