Design, synthesis of novel benzimidazole derivatives as ENL inhibitors suppressing leukemia cells viability via downregulating the expression of MYC

Discovering potential inhibitors of the YEATS domain of YEATS2 through virtual screening, molecular optimization and molecular dynamics simulations

“…2, 3 , IC 50 = 8.3 μM). 21 Garnar-Wortzel et al executed the screening of nearly 300 000 small molecules and developed a selective ENL/AF9 YEATS domain inhibitor 4 (Fig. 2, IC 50 = 25 nM) and ENL degrader 5 (Fig.…”

Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable In Vivo Studies: Discovery of TDI-11055

“…14,15 Other derivatives with the benzimidazole-amide scaffold were reported from crystallography-based screen and rational design. 16,17 Additional chemotypes such as isoxazoleamides and piperazine-ureas were later identified, having comparable or slightly weaker potency than the benzimidazole-amide inhibitors. 18,19 More recently, alternative chemo- types with more potent in vitro potency such as amidotriazolopyridines (Cmp 11 ENL IC 50 < 0.1 μM by AlphaScreen assay) and amido-imidazopyridines (SR-0813 ENL IC 50 = 0.025 μM by HTRF) were identified.…”

“…The peptide-based inhibitor, XL-13m (ENL IC 50 = 0.56 μM by competitive photo-cross-linking assay), was developed with an expanded π system replacing the crotonyl group on the Lys side chain that forms π-stacking interaction with the aromatic triad in the Kac pocket . The first small molecule chemical probe, SGC-iMLLT (ENL IC 50 = 0.26 μM by AlphaScreen assay), an analog optimized from a medium-throughput screening hit, has a benzimidazole-amide scaffold that binds to the Kac pocket, where the amide acts as an acetyl-lysine mimetic in a flipped orientation and forms a π-stacking interaction with the aromatic triad. , Other derivatives with the benzimidazole-amide scaffold were reported from crystallography-based screen and rational design. , Additional chemotypes such as isoxazole-amides and piperazine-ureas were later identified, having comparable or slightly weaker potency than the benzimidazole-amide inhibitors. , More recently, alternative chemotypes with more potent in vitro potency such as amido-triazolopyridines (Cmp 11 ENL IC 50 < 0.1 μM by AlphaScreen assay) and amido-imidazopyridines (SR-0813 ENL IC 50 = 0.025 μM by HTRF) were identified. , However, the in vitro potency of these compounds did not translate to cellular efficacy in ENL-dependent AML cells or in vivo efficacy in animal models of AML. , While these published compounds convincingly supported the tractability of the ENL YEATS domain for drug discovery, each of them exhibited either suboptimal cellular activity or poor pharmacokinetic properties that limited further use for fully exploring the translational potential of ENL inhibition in cancer models.…”