Drug Discovery and Chemical Biology of Cancer Epigenetics Scott Ribich, Darren Harvey, Robert A. Copeland  Cell Chemical Biology  Volume 24, Issue 9, Pages 1120-1147 (September 2017) DOI: 10.1016/j.chembiol.2017.08.020 Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 1 Modification of Chromatin Structure by CMPs Simplified schematic of nucleosomes, composed of histone proteins (represented by the red, yellow, green, and blue octamers) wound by DNA (blue). Green and orange boxes represent the enzymes that generate/remove post-translational modifications on the histones, such as methylation (me) and acetylation (ac). The blue box represents ATPase hydrolysis-dependent helicases that can catalyze changes of histone components (e.g., ATRX) or change the relative topography of the DNA-histone interactions (e.g., mSWI/SNF). The purple box represents enzymes responsible for generation/removal of DNA methylation at CpG islands. DNMT, DNA methyltransferase; HAT, histone acetyltransferase; HDAC, histone deacetylase; KDM, lysine demethylase; PAD, protein arginine deininase; PKMT, protein lysine methyltransferase; PRMT, protein arginine methyltransferase; TET, ten-eleven translocation. Cell Chemical Biology 2017 24, 1120-1147DOI: (10.1016/j.chembiol.2017.08.020) Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 2 Examples of CMP-Modulator Interactions (A) Crystal structure of histone lysine methyltransferase EHMT2 (light blue) and SAM (orange) with inhibitor UNC0638 (pink) bound within the lysine binding channel (PDB: 3RJW). (B) Crystal structure of a ternary complex of PRMT5:MEP50 (light blue), EPZ015666/GSK3235025 (pink), and SAM (orange) (PDB: 4X61). (C) Crystal structure of Menin (light blue) in complex with MI-503 (pink) bound at the MLL1 binding surface (PDB: 4X5Y). (D) Crystal structure of bromodomain BRD4 (light blue) with inhibitor JQ1 (pink) bound in the acetyl-lysine binding pocket (PDB: 3MXF). Cell Chemical Biology 2017 24, 1120-1147DOI: (10.1016/j.chembiol.2017.08.020) Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 3 Synthetic Lethal Relationship with CMPs (A) Schematic of paralog synthetic lethality. Blue represents subunits of an essential CMP complex, with red denoting redundant paralogs that are necessary for appropriate complex function. In a wild-type cell, loss of paralog #2 by knockout or inhibition is tolerated due to presence of paralog #1. However, in a cancer cell that has lost paralog #1, the cell is vulnerable to knockout or inhibition of paralog #2 as it would remove all activity of the CMP complex. (B) Schematic of classical synthetic lethality. Blue arrows represent genes in pathway A, where normal gene A1 function is perturbed in cancer (either by loss of gene A1 or the generation of an aberrant fusion protein). In one scenario, this mutation in gene A1 can generate increased activity of a separate gene pathway (denoted by red arrows), and the cancer cell is specifically sensitive to inhibition of genes B1 or B2. In a second scenario, the mutation in gene A1 decreases the downstream activity of pathway A and sensitizes cells to inhibition of gene A2. (C) Schematic of collateral synthetic lethality. The purple arrow represents a tumor-suppressor gene (denoted “Tumor Suppressor (TS)”) which is homozygously deleted in a cancer cell. This deletion also removes an unrelated neighboring gene “A1,” which can create a metabolic or epigenetic dependency on a separate gene, similar to as in (B), although the synthetic lethality occurs as a result of deletion of the passenger gene instead of the tumor suppressor. Cell Chemical Biology 2017 24, 1120-1147DOI: (10.1016/j.chembiol.2017.08.020) Copyright © 2017 Elsevier Ltd Terms and Conditions