Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors

Area of Science:

• Immunology
• Biochemistry
• Medicinal Chemistry

Background:

• Signal Peptide Peptidase Like 2a (SPPL2a) is an intramembrane aspartyl protease crucial for B-cell and dendritic cell function.
• SPPL2a is an attractive target for immune system modulation, but selective inhibitors are scarce.
• Previous work identified SPL-707, demonstrating SPPL2a inhibition reduces B-cells and myeloid dendritic cells in mice via CD74/p8 accumulation.

Purpose of the Study:

• To discover and develop novel, selective hydroxyethylamine-based inhibitors of SPPL2a.
• To optimize a screening hit into a potent and selective SPPL2a inhibitor.
• To evaluate the in vivo efficacy of the developed inhibitors.

Main Methods:

• Iterative medicinal chemistry optimization of a lipophilic screening hit.
• Synthesis and characterization of novel hydroxyethylamine derivatives.
• In vivo assessment of SPPL2a substrate processing inhibition and its effects on immune cells.

Main Results:

• Discovery of a series of novel hydroxyethylamine-based SPPL2a inhibitors.
• Identification of compound 15 (SPL-410) as a highly potent and selective inhibitor.
• Demonstration of in vivo inhibition of CD74/p8 fragment processing by SPL-410 at a 10 mg/kg oral dose in mice.

Conclusions:

• Hydroxyethylamine scaffold is suitable for developing potent and selective SPPL2a inhibitors.
• SPL-410 represents a promising lead compound for further investigation in immune modulation.
• Pharmacological inhibition of SPPL2a can effectively modulate immune cell populations in vivo.