Alteration of small GTPase functions is a hallmark of genetic and sporadic human diseases, making GTPase family members attractive though understudied targets. Specifically, the Ras superfamily of GTPases includes Arf, Rho, Ras and Rab GTPase subfamilies. Besides, they regulate a broad range of cellular processes ranging from membrane trafficking to the control of cell proliferation. In a cellular context, GTPases are molecular regulators that switch between GDP (inactive) and GTP (active) bound conformational states. To date, inhibitors of small GTPase function have focused on blocking membrane recruitment. Moreover, among the Rab GTPases, Rab7 occupies a critical nexus in the endocytic pathway where it governs cellular processes. Furthermore, mapping the functionality of GTPases through small molecule inhibitors represents an underexplored area in large part due to the lack of suitable compounds. CID-1067700 is a pan GTPase inhibitor and competitively inhibits Ras-related in brain 7 (Rab7).

CID-1067700 (ML282) is a pan GTPase inhibitor and competitively inhibits Ras-related in brain 7 (Rab7) with a Ki of 13 nM. In addition, CID-1067700 shows inhibitory activity against nucleotide binding by Rab7. Meanwhile, CID-1067700 has Kds of 100 nM and 40 nM for BODIPY-GTP and BODIPY-GDP, respectively. Furthermore, CID-1067700 binds Rab7 with a high affinity and blocks Class switch DNA recombination (CSR) in B cells via targeting Rab7. Nonetheless, CID-1067700 is the first example of a competitive guanine nucleotide-binding inhibitor characterized by any member of the Ras-super family of GTPases. Finally, CID 10677000 is an inhibitor with demonstrated activity against any member of the Rab subfamily of GTPases. All in all, CID-1067700 is a pan GTPase inhibitor, and competitively inhibits Rab7.



Agola JO, et al. ACS Chem Biol. 2012 Jun 15;7(6):1095-108.