GAP-assoc p62 Inhibitors

Chemical inhibitors of GAP-assoc p62 can disrupt its activity through a variety of molecular mechanisms, primarily by targeting pathways that are upstream of GAP-assoc p62. For instance, Wortmannin and LY294002 are compounds that inhibit phosphoinositide 3-kinases (PI3Ks), a group of enzymes involved in the initiation of the Akt signaling pathway. Since GAP-assoc p62 operates downstream of this pathway, the inhibition of PI3K by these compounds results in a reduction of Akt phosphorylation, which in turn diminishes the activation of GAP-assoc p62. Similarly, Spautin-1, which induces the degradation of PI3K, leads to reduced PI3K activity and thus less activation of the downstream components including GAP-assoc p62. Perifosine and Miltefosine, both alkylphospholipids, inhibit the activation of Akt, thereby preventing the phosphorylation and subsequent activation of GAP-assoc p62.

In addition to the PI3K/Akt pathway inhibitors, compounds that target mTOR, a key part of the same pathway, also play a role in regulating the activity of GAP-assoc p62. Rapamycin and its analogs, such as PP242 and Palomid 529, inhibit mTOR by different mechanisms; Rapamycin binds to mTOR complex 1 (mTORC1), while PP242 and Palomid 529 target the ATP-binding site of mTOR or both mTORC1 and mTORC2, respectively. This inhibition leads to reduced downstream signaling, which includes the activity of GAP-assoc p62. Other Akt-specific inhibitors, such as Triciribine, MK-2206, GSK690693, and AZD5363, directly prevent Akt phosphorylation and activation. By selectively inhibiting Akt, these compounds ensure that the phosphorylation-dependent activation of GAP-assoc p62 does not occur, effectively reducing its functional activity within the cell. Each of these inhibitors operates by impeding the signaling required for GAP-assoc p62 activation, although by different molecular targets and mechanisms.