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

Abstract

The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy.

Hot Spot Analysis of YAP-TEAD Protein-Protein Interaction Using the Fragment Molecular Orbital Method and Its Application for Inhibitor Discovery

“…It retained hydrophobicity-driven interactions with Lys274 for TEAD1 with electrostatic forces of −7.356 kcal/mol. Moreover, as described above, YAP Ser94, Phe96, Arg89, and Phe95 have been revealed as critical binding residues in YAP-TEAD1 PPIs by previous mutagenesis studies [26,29,30,59,63,64]. Phe96 interacts with Lys274 via electrostatic interactions.…”

The essential role of TAZ in normal tissue homeostasis

“…Therefore, pharmacological development of TAZ inhibitors for cancer treatment deserves a great deal of attention with respect to prediction of toxicity and side effects on tissue homeostasis. It is indispensable to develop selective inhibitors or activators that target specific binding sites between TAZ and its interacting partner, which may not interfere with normal tissue homeostasis and may contribute to desirable therapeutic effects (Pobbati and Rubin 2020). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.…”

An Updated Understanding of the Role of YAP in Driving Oncogenic Responses

“…The third interface assumes importance because it determines the affinity of binding between molecular partners, while the second interface is home of peptides and small molecules bindings that may act as disruptor of YAP/TEAD interaction. These works are carried out by Hong et al and Pobbati et al groups who recently identified another pocket, showed as target for drugs with great potential in the impairment of YAP/TEAD complex formation [ 30 , 31 ].…”