Signal peptide peptidase-like 2a (SPPL2a) is a member of the signal peptide peptidase like protease (SPPL) family. Specifically, SPPL2a encodes lysosome/late endosomal membrane protein and has conserved active-site motifs “YD” and “gxgd” in the adjacent transmembrane domains (TMD). Besides, the protein plays a role in innate and adaptive immunity by cleaving TNFα in activated dendritic cells. Moreover, regulatory membrane proteolysis (RIP) is an extracellular environment that controls the process of cell to cell communication. The most prominent and characteristic member of this enzyme is γ-secretase, an amyloid precursor of aspartic I-CLiP, which produces a β-peptide protein (APP). Furthermore, SPPL2a is an enzyme related to presenilin and a catalytic subunit of γ-secretase. SPPL2a is relevant to the regulation of adaptive immunity, so inhibition of SPPL2a may reduce its antigen presentation ability. SPL-707 is a potent, selective, and orally available SPPL2a inhibitor.

SPL-707 is a potent, selective, and orally available SPPL2a inhibitor.

How does SPL-707 work on the target? Let’s study it together. In the beginning, SPL-707 is an orally active, selective SPPL2a inhibitor with an IC₅₀ of 77 nM for hSPPL2a. Meanwhile, SPL-707 inhibits γ-secretase (IC₅₀=6.1 μM) and SPP (IC₅₀=3.7 μM). Nonetheless, SPL-707 has the potential for autoimmune disease research by targeting B cells and dendritic cells.

In the second place, SPL-707 inhibits mouse SPPL2a (IC₅₀=0.18 μM), rat SPPL2a (IC₅₀=0.056 μM).  Particularly, SPL-707 inhibits human SPPL2a (IC₅₀=0.16 μM), human SPPL2b (IC₅₀=0.43 μM) by a high content imaging assay (HCA)

Last but not the least, SPL-707 with 3-30 mg/kg by orally (b.i.d.) for 11 days leads to a reduction in B cells and myeloid dendritic cells without affecting γ-secretase activity. Particularly, SPL-707 has a CL of 6 mL/min•kg, and an AUC of 8787 h•nM by 3 mg/kg of po and 1 mg/kg of iv. Interestingly, SPL-707 achieves full inhibition of CD74/p8 processing in spleen in female Lewis rats.

All in all, SPL-707 is a potent, selective, and orally available SPPL2a inhibitor.

References:

Velcicky J, et al. J Med Chem. 2018 Feb 8;61(3):865-880.