VPS37C Inhibitors

Chemical inhibitors of VPS37C employ various mechanisms to disrupt the protein's function, which is integral to the endosomal trafficking system within cells. Concanamycin A and Bafilomycin A1 target the vacuolar type H+-ATPase (V-ATPase), inhibiting the acidification of endosomes and lysosomes. This inhibition raises the pH within these organelles, thereby impeding VPS37C's role in the endocytic pathway, as the protein relies on a certain acidic environment to mediate vesicular trafficking. Similarly, Chloroquine and its analogue Hydroxychloroquine, along with NH4Cl, also disrupt the acidic environment within endosomes and lysosomes. By increasing the pH, these chemicals interfere with the normal function of VPS37C, which is contingent on the organelle's acidity for sorting and trafficking processes.

Other inhibitors, such as Dynasore and MiTMAB, act by targeting dynamin, a GTPase essential for the detachment of clathrin-coated vesicles from the membrane. Inhibiting dynamin function prevents the proper formation of endosomal vesicles, which indirectly affects VPS37C by hindering the vesicle's trafficking and delivery to their designated locations within the cell. Monodansylcadaverine, while primarily known as an autophagic marker, also plays a role in inhibiting VPS37C by disrupting the autophagic process, which can be connected to the endosomal sorting and trafficking. Genistein, by inhibiting tyrosine kinases, affects signaling pathways that can modulate endocytic trafficking, and thus, could indirectly modulate the activity of VPS37C. Wortmannin and LY294002, both PI3K inhibitors, disrupt early endosomal trafficking by impeding the endosomal sorting complex required for transport (ESCRT) machinery, which is essential for VPS37C's function in sorting proteins within endosomes. Lastly, EIPA, by preventing the re-acidification of intracellular organelles, alters the endosomal pH, thereby disrupting the functional environment necessary for VPS37C's role in protein sorting and trafficking.