Supplementary material. Identification of SET/EED dual binders as PRC2 innovative inhibitors.

Figure S1. 2D
chemical structure of the inhibitor
(3R,4S)-1-[(2-methoxyphenyl)methyl]-N,N-dimethyl-4-(1-methylindol-3-yl)pyrrolidin-3-amine
(LQD) co-crystallized in the embryonic ectoderm development (EED) model (PDB
ID 5U69).
Figure S2. 3D
representation of pharmacophore model in the binding pocket of EED. Chemical
features are color-coded: yellow, green and red spheres represent hydrophobic
features (HY), H-bond donors (HBD), and H-bond acceptors (HBA), respectively.
Figure S3. 2D
chemical structure of the S-Adenosyl-L-Homocysteine (SAM) co-crystallized in
the SET model (PDB ID 5HYN).
Figure S4. 3D
representation of pharmacophore model in the binding pocket of SET. Chemical
features are color-coded: yellow spheres represent hydrophobic features (HY),
green and red arrows represent H-bond donors (HBD) and H-bond acceptors
(HBA), respectively.
Figure S5. 2D
representation of the underlying binding interactions of the hit compounds A)
1, B) 2, C) 3, D) 4 and E) 5 in the embryonic ectoderm development (EED)
pocket. The H-bonds are depicted as green and red dash arrows, depending on
the behavior of the ligand as donor or acceptor, respectively. Conversely,
the main hydrophobic and aromatic interactions were depicted as yellow lines
and blue arrows, respectively.

Figure S6. 2D representation of the underlying
binding interactions of the hit compounds A) 1, B) 2, C) 3, D) 4 and E) 5 in
the SET pocket. The H-bonds are depicted as green and red dash arrows,
depending on the behavior of the

ligand as donor or
acceptor, respectively. Conversely, the main hydrophobic and aromatic
interactions were depicted as yellow lines and blue arrows, respectively.
Table S1. Protein
Data Bank (PDB) ID and Diffraction-component Precision Index (DPI) score for
both targets.
Table S2. Set of 250
actives compounds of SET.
Table S3. Set of 154
actives compounds of embryonic ectoderm development (EED).

Table S4. List of the shared hits, reported
their ADME-related parameters computed inside the Multi-Target Ligand
(Mu.Ta.Lig.) Chemotheca.