Researchers at Imperial College London and collaborating institutions have developed the first cell-active, rationally designed covalent inhibitors of the RAB27-effector protein–protein interaction. These new chemical probes could help researchers investigate how RAB27 proteins control intracellular trafficking and contribute to disease.
Published in the Journal of the American Chemical Society, the study describes a new approach to targeting RAB27A and RAB27B, small GTPases that regulate vesicle movement inside cells. These proteins are involved in cellular communication, immune responses, tumour metastasis, and chronic inflammation.
The team combined an electrophile-first biochemical screen with structure-guided drug design to create a new class of acrylamide-based covalent inhibitors. These target a non-conserved cysteine residue, Cys123, near the RAB27-effector interaction interface. X-ray crystallography guided optimisation, and experiments confirmed the probes selectively target RAB27A and RAB27B in cells.
The study also highlighted issues with a previously reported inhibitor, Nexinhib-20, showing it was cytotoxic and acted non-selectively. The new research provides a toolbox of selective, cell-active RAB27 probes, including an inactive enantiomeric control, to enable further investigation of RAB27 biology and its potential as a therapeutic target.
