Arf2 Inhibitors

Chemical inhibitors of ARF2 operate through various biochemical mechanisms to obstruct the activation and function of this protein. Brefeldin A directly targets ARF2 by preventing the exchange of GDP for GTP, a necessary step for ARF2 to become active, ultimately leading to the disruption of vesicle formation within cells. SecinH3, on the other hand, inhibits cytohesins, which are guanine nucleotide exchange factors (GEFs) essential for ARF2 activation. As SecinH3 impairs GEF activity, ARF2 activation is reduced due to the decreased exchange of GDP for GTP. Golgicide A takes a more targeted approach by inhibiting GBF1, a specific GEF for the closely related ARF1 protein, which in turn can affect ARF2 activity due to shared regulatory mechanisms within the ARF family. Exo2 and LG186 extend this inhibition strategy by targeting Sec7 domain-containing proteins and the BIG1 and BIG2 GEFs, respectively, further reducing ARF2 function by impeding the activation process that relies on GEFs.

Additional inhibitors work indirectly to affect ARF2's role in vesicle trafficking. Hydroxyquinoline chelates metal ions, which are crucial for various enzymes, including those that facilitate ARF2's function, thus indirectly inhibiting ARF2. Similarly, Pitstop 2 disrupts clathrin-mediated endocytosis, a process with which ARF2 is associated, thereby indirectly impeding ARF2's function in vesicle formation. Dynamin, a critical protein for vesicle scission, is the target of Dyngo-4a and MiTMAB, which by inhibiting dynamin, can secondarily limit ARF2's role in endocytosis. Furthermore, ML141, which selectively inhibits the GTPase Cdc42, can have a cascade effect that disrupts the broader GTPase-mediated signaling pathways in which ARF2 participates. IKK-16 acts on the IκB kinase, part of the NF-κB signaling pathway, and can thus influence ARF2's regulatory functions indirectly. Lastly, CID1067700 serves as a competitive antagonist to GTPases, including ARF2, by competing for GTP binding sites and preventing the activation of ARF2 necessary for vesicle trafficking regulation.