Small-molecule tools for YEATS domain proteins

Genetically Encoded Epitope Tag for Probing Lysine Acylation-Mediated Protein–Protein Interactions

“…For example, histones, which are scaffolding proteins for chromatin compaction in eukaryotic nuclei, are subjects to diverse PTMs . These histone marks can serve as docking hubs for the binding of protein effectors (or readers) to chromatin, enabling transmission of messages carried by the marks to downstream chromatin-templated events. − YEATS domains are a family of newly identified readers of histone lysine acetylation (Kac) and crotonylation (Kcr). − The human genome encodes four YEATS domain-containing proteins (YCPs), namely, AF9, ENL, GAS41, and YEATS2. , Recent studies have revealed associations between aberrant YEATS-dependent readouts of histone Kac/Kcr marks and human diseases, especially cancer. − Tools and/or methods that facilitate the interrogation of YEATS–Kac/Kcr interactions in different biological contexts would be helpful to comprehensively understand the roles played by YEATS domains in chromatin biology. − …”

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

“…9,10 Thus, pharmacological inhibition of the ENL YEATS domain reader activity represents a promising therapeutic strategy for AML and potentially other cancers. 11,12 Analysis of the crystal structures of the ENL YEATS domain shows that it recognizes histone lysine acetylation and crotonylation with a tunnel-like acetyl-lysine (Kac) pocket formed by three loops L1/L4/L6 and side chains of the aromatic triad residues Phe28/Phe59/Tyr78. 5 Several chemical probes for ENL YEATS have been reported in the literature (Figure 1).…”

“… Additionally, the wild-type ENL is required for the maintenance of AML that carries MLL fusions or NPM1 mutations. Mutational disruption of the interaction between the ENL YEATS domain and acylated histones has been shown to reduce the elongation of RNA polymerase II at ENL-target genes, leading to suppression of oncogenic gene expression programs in these AML subsets. , Furthermore, a series of hotspot mutations in the ENL YEATS domain have been found in patients with AML and Wilms tumors. , These mutations increase ENL’s transcriptional activity and drive hyperactivation of key cancer genes, and such a function requires the reader activity of ENL. , Thus, pharmacological inhibition of the ENL YEATS domain reader activity represents a promising therapeutic strategy for AML and potentially other cancers. , …”