Table 1.

Chemical strategies and principles applied to the discovery of antagonists for cavity insertion methyllysine binders and surface groove methyllysine binders.

	Cavity Insertion Binders	Surface Groove Binders
Hit Discovery & Screening Strategies	Screen focused small molecule or fragment libraries Employ target class cross screening Utilize structure-based design for hit optimization	Apply structure-based design Screen peptide or peptoid libraries
Design Principles	Exploit cation-π and H-bonding interactions in aromatic cage Utilize conformational constrained alkyl amines	Use available Kme peptide SAR Target binding sites adjacent to aromatic cage Introduce unnatural amino acids, Kme mimics, and non-peptidic features
Major Challenge	Fragment-like size may result in low affinity	Low cell permeability may decrease overall utility
Example	L3MBTL1 + H4K20me2 (pdb 2PQW)	CBX7 + H3K27me3 (pdb 4X3K)