Many anti-cancer drugs exert their cytotoxic effects by indirectly up-regulating the pro-apoptotic BH3-only proteins or by decreasing the expression of the pro-survival BCL-2 proteins. In contrast, BH3-mimetics directly antagonise the pro-survival BCL-2 proteins, bypassing defects in upstream signalling pathways such as those mediated by p53, which is commonly inactivated in cancers. Direct activators of BAX or BAK have also been developed as an alternate mechanism for inducing apoptosis.