Transcription factor protein-protein interaction disruptors: heavier, more hydrophobic, and more rigid than regular drugs. Anticancer indications: a/ BRD4/histone interaction disruptor: BRD4 binds to acetylated lysine residues in histone tails, which act as activation markers for gene expression. (+)-JQ1 was modeled to fit a hydrophobic cavity in the BRD4 domain that accommodates acetylated lysines. Potential indications are squamous cancer and acute myeloid leukemia . b/ HDM2(MDM2)/p53 interaction disruptors: Human or mouse double minute 2 protein binds to tumor suppressor p53, increasing its degradation. Tetra-substituted imidazole, Nutlin-3, disrupts complexes with nanomolar affinity . Subsequent attempts at computational optimization based on existing PPI descriptors and X-ray crystallography have generated compounds with low/sub-micromolar affinities PB11 and BDM_4605 [60,72]. Potential indications are all p53-related cancers. c/ Bcl-2(Bcl-xL)/Bax(Bak) interaction disruptors: Bcl-2 or Bcl-xL binds to the BH3 (Bcl2-homology 3) domain of pro-apoptotic Bax and Bak proteins, preventing apoptosis. BH3-mimetic ABT-737 disrupts complexes with sub-micromolar affinity, inducing apoptosis. Potential indications are small-cell lung carcinoma and lymphoma . Other indications: d/ STAT3 is a latent cytoplasmic transcription factor transducing signals from the cell membrane to the nucleus. STAT3 can dimerize via reciprocal interaction of its Src homology 2 domain (SH2), upon phosphorylation of a conserved tyrosine within the SH2 domain. STA-21 inhibits cytokine-dependent nuclear translocation of Stat3 in normal human keratinocytes in vitro by impeding STAT3 DNA binding and dimerization with mid-micromolar potency .