Diablo Inhibitors

Chemical inhibitors of Diablo function by interfering with its interaction partners, primarily Inhibitor of Apoptosis Proteins (IAPs), thereby promoting apoptosis. Embelin directly binds to XIAP, one of the IAPs that form a complex with Diablo, thus inhibiting its anti-apoptotic activity. A similar mechanism is employed by GDC-0152, which also inhibits XIAP, preventing it from forming a complex with Diablo and thereby promoting apoptosis. SM-164 takes a broader approach, targeting multiple IAPs including XIAP, cIAP1, and cIAP2. This multi-target inhibition further disrupts the regulatory role of Diablo, facilitating apoptotic processes. AT-406 acts selectively on IAPs, particularly XIAP, as well as cIAP1 and cIAP2, negating the inhibitory action of Diablo on apoptosis. The compound LCL161, another IAP antagonist, binds to and inhibits cIAP1 and cIAP2, leading to apoptosis activation, which under normal circumstances could be restrained by Diablo's interaction with these proteins. Birinapant (also known as TL32711) is a bivalent SMAC mimetic that targets IAPs for inhibition. By doing so, it disrupts the interaction between Diablo and IAPs, enabling the apoptotic signaling cascade to proceed. BV-6 similarly functions as a SMAC mimetic that antagonizes IAPs, facilitating caspase activation and subsequent apoptosis, thereby indirectly reducing Diablo's capacity to inhibit apoptosis. Minnelide, and its active form triptolide, modulate the transcription of genes involved in the anti-apoptotic pathway. They result in downregulation of IAPs, thus indirectly counteracting the effect of Diablo. UMI-77 targets Mcl-1, disrupting its interaction with BAK, a pro-apoptotic protein. As Diablo modulates apoptosis through IAPs, the inhibition of Mcl-1 by UMI-77 can promote the activation of pro-apoptotic proteins that are regulated by Diablo. Lastly, TW-37 targets Bcl-2, Bcl-xL, and Mcl-1, which are all part of the apoptotic regulatory network that interacts with Diablo; inhibiting these proteins can amplify the apoptotic signal, thus diminishing Diablo's ability to inhibit this process.