Atg9b Inhibitors

Chemical inhibitors of Atg9b target various stages of the autophagy pathway to impede its function. 3-Methyladenine and Wortmannin are both inhibitors of Class III phosphatidylinositol 3-kinase (PI3K), an enzyme integral to the initiation of autophagy. These inhibitors prevent the formation of autophagosomes, thereby inhibiting the incorporation of Atg9b into the autophagosomal membrane. Similarly, LY294002, another PI3K inhibitor, hinders the vesicle nucleation process, which is a prerequisite for Atg9b activity. SAR405 and PIK-III, which specifically target the Vps34 complex and Vps34 PI3K respectively, critically affect the autophagic vesicle nucleation, leading to a functional inhibition of Atg9b. Spautin-1 indirectly inhibits Atg9b by promoting the degradation of PI3K and disrupting the autophagy pathway, thereby affecting Atg9b's role in autophagosome formation.

Furthermore, Hydroxychloroquine and Chloroquine both raise lysosomal pH, which disrupts autophagosome degradation, a process in which Atg9b is involved. This alteration in pH indirectly inhibits the function of Atg9b by interfering with the maturation of autophagosomes. Bafilomycin A1 and Concanamycin A, both V-ATPase inhibitors, prevent the acidification of lysosomes, crucial for autophagosome-lysosome fusion, indirectly inhibiting Atg9b by disrupting the autophagic flux. Torin 1 and Ku-0063794, as mTOR inhibitors, induce autophagy initially; however, with prolonged exposure, they inhibit autophagosome maturation. This disruption to the normal autophagy process serves to functionally inhibit Atg9b by interfering with its role in autophagosome maturation, demonstrating how the modulation of upstream autophagic signals and cellular conditions can lead to the functional inhibition of Atg9b.