Developing more specific targeted therapies for AML. (A) Disrupting specific epigenetic programs. Targeting TFs would enable disruption of more specific oncogenic programs, however, drugs against TFs are difficult to develop. To circumvent this limitation, new therapies could either (1) block specific domains on generic epigenetic proteins that interact with an oncogenic TF or (2) disrupt specific submodules of large epigenetic complexes, which are recruited by a particular TF. Either of these approaches could retain druggability, while also disrupting a more AML-specific program. (B) Disrupting DNA binding of epigenetic proteins. TFs and epigenetic proteins can be recruited to DNA by specific DNA sequences. Inhibitors that interact with these DNA sequences could potentially block binding of a TF or epigenetic protein, resulting in disruption of a more AML-specific transcriptional program. (C) Degradation of epigenetic proteins or oncogenic drivers. Traditional drug development requires the functional domain of a target protein to have a structure amenable to inhibition. Proteolysis-targeting chimera (PROTAC)-based degradation strategies do not require the specific functional domain to be druggable; instead small molecules or peptides can be designed against any region of the protein of interest. These molecules are fused to a linker that brings the protein into close proximity with an E3 ubiquitin ligase. This proximity causes ubiquitination, resulting in its degradation of the target protein. This is likely to dramatically expand the number of oncogenic proteins that are druggable. DBD, DNA-binding domain.