TEAD–YAP Interaction Inhibitors and MDM2 Binders from DNA‐Encoded Indole‐Focused Ugi Peptidomimetics

Abstract

DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or "hot spot", regions of protein-protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide "hexT", encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.

Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex

“…A DNA-encoded, indole-focused combinatorial library of 8112 compounds was screened against TEAD with the goal of identifying PPIDs that disrupt the YAP-TEAD interaction [ 37 ]. The indole-focused library is expected to exploit the crucial PPI interactions mediated by the indole ring of the tryptophan residues in proteins.…”

“…As only the transactivation domain of TEAD was used in this assay, it will be interesting to deduce whether the compound induces a conformational change in TEAD upon binding. Unfortunately, in HEK 293 cells, compound 9 did not inhibit the expression of CTGF, a YAP-TEAD target gene [ 37 ]. Intriguingly, the efficacy is better when compound 9 is combined with a hippo kinase inhibitor.…”

Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

“…A recent study identified molecules disrupting TEAD-YAP interactions by screening a DNA-encoded library. Two inhibitors against the protein-protein interaction exhibited IC 50 s of 6.75 µM and 5.65 µM, respectively [82]. TEADs contain a conserved hydrophobic pocket in its YAP-binding domain (YBD).…”

Scanning Protein Surfaces with DNA‐Encoded Libraries

“…hTEAD4/YAP : Dysregulation of protein–protein interactions between transcriptional enhancer factor‐1 domains (TEAD1‐4) and co‐transcription factor Yes‐associated protein (YAP), late Hippo signaling pathway effectors, is associated with oncogenic mechanisms [105–107] . Recently, screening of a small thymidine‐initiated DEL (tiDEL) of peptidomimetics against YAP‐interacting domain of human TEAD4 (hTEAD4) led to the identification of two PPI inhibitors 11 (Figure 5, IC 50 =6.75 μM) and 12 (IC 50 =5.65 μM) [108] . This library was synthesized around the tryptophan side chain as an “anchor motif” with indoles introduced into the library via Ugi four‐component reaction as tryptophan mimetics and CuAAC for library diversification.…”

“…Both compounds showed hTEAD4/YAP interaction inhibition, however, only compound 11 exhibited inhibition of the palmitic acid‐hTEAD4 interaction that takes place in the so called “central pocket” of hTEAD. Notably, compound 11 demonstrated perturbation of the expression of CTGF gene which is under control of these Hippo pathway effectors [108] …”