Structure-Based Discovery of GTP-Enhanced Rab10 Modulators and Their Effects on Alzheimer Disease-Relevant Cellular Phenotypes

R3 is a GTP-enhanced Rab10 modulator that, in APP/presenilin-1 CHO cells and neuronal PC12 cells, reduces APP-CTFs and tau phosphorylation while reshaping endosomal organization.

• Why it matters: Rab10 trafficking is linked to Alzheimer disease, but there are limited pharmacological tools to probe its function and nucleotide-dependent behavior in relevant cellular phenotypes.
• What they did: The team screened more than 80 million compounds via structure-based virtual screening, selected five candidates (R1–R5), validated binding with docking/MD and SPR, then tested R3 and R1–R3 in cell assays including GTP quantification, endosome markers, APP processing, and NGF withdrawal.
• The result: SPR showed micromolar apparent affinities for R1–R4 without added GTP and nanomolar under GTP-containing conditions, and R3 produced dose- and time-dependent reductions in GTP-bound Rab10, enabling AD-relevant phenotype modulation.

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