Abstract: The Hippo signaling pathway is a highly conserved regulatory network that controls cell proliferation and apoptosis. Dysregulation of this pathway, often through mutations in upstream components like NF2 or LATS1/2, leads to the aberrant nuclear accumulation of the transcriptional coactivators YAP and TAZ. In the nucleus, YAP/TAZ bind to TEAD transcription factors to drive oncogenic gene expression, making the YAP/TAZ-TEAD complex a highly attractive therapeutic target for various solid tumors. However, developing small molecules that directly disrupt this broad and shallow protein-protein interaction (PPI) has historically been challenging. IAG933 has emerged as a pioneering, first-in-class direct small-molecule protein-protein interaction disruptor (PPID) that selectively targets interface 3 of the YAP-TEAD complex. Currently in Phase I clinical trials for advanced solid tumors harboring Hippo pathway alterations, IAG933 represents a significant breakthrough in targeted cancer therapy, demonstrating the feasibility of directly drugging the YAP-TEAD surface interface.
1. Introduction
The evolutionarily conserved Hippo signaling pathway plays a fundamental role in regulating tissue homeostasis, organ size, and cell proliferation [1][2]. The core of this pathway consists of a kinase cascade, including MST1/2 and LATS1/2, which normally phosphorylates and sequesters the downstream effector proteins Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in the cytoplasm [1]. When the Hippo pathway is genetically inactivated or dysregulated—frequently observed in various human malignancies—unphosphorylated YAP and TAZ translocate into the nucleus. Because YAP and TAZ lack their own DNA-binding domains, they must interact with transcription factors, predominantly the TEAD (TEA/ATTS domain) family (TEAD1-4), to induce the expression of pro-proliferative and anti-apoptotic genes [2].
The critical role of the YAP/TAZ-TEAD interaction in tumor development and acquired therapy resistance has made it a prime target for pharmacological intervention [2]. While early drug discovery efforts focused on allosteric inhibitors that bind to a central lipid pocket on TEAD, directly disrupting the YAP/TAZ-TEAD protein-protein interaction (PPI) at the surface has been a major challenge [2]. IAG933, developed by Novartis, is a novel, direct small-molecule PPI disruptor (PPID) that has successfully bridged this gap, offering a new therapeutic avenue for Hippo-altered solid tumors [1][2].
2. Pharmacological Activity
IAG933 is a potent and selective small-molecule inhibitor designed to disrupt YAP/TAZ-TEAD protein-protein interactions [1]. Preclinical evaluations of IAG933 and its structural analogs have demonstrated promising in vitro and in vivo biological activities, effectively inhibiting YAP-TEAD-dependent gene expression in cancer models such as NCI-H2052 cells [2].
Translating these preclinical successes into clinical applications, IAG933 entered human testing in 2021 [2]. It is currently being evaluated in a Phase I clinical trial (NCT04857372) [1]. The clinical investigation specifically targets patients with advanced solid tumors that are enriched for Hippo pathway alterations. This includes malignant mesothelioma and other solid tumors characterized by NF2 mutations, LATS1/2 mutations, or YAP/TAZ gene fusions [1]. As the only surface inhibitor of the YAP/TAZ-TEAD complex to enter clinical testing to date, IAG933 serves as a critical test case for the efficacy of direct PPIDs in oncology [2].
3. Molecular Mechanism of Action
The molecular mechanism of IAG933 centers on the direct and selective pharmacological disruption of the YAP-TEAD interface [1]. Structural biology studies have revealed that YAP and TEAD form three distinct interaction interfaces (Interfaces 1, 2, and 3) [2]. Interface 3, also known as the omega-loop (Ω-loop) region, features a deep and broad surface pocket on TEAD that interacts with key hydrophobic side chains of YAP (such as Met86, Leu91, and Phe95) and TAZ [2].
Unlike allosteric inhibitors that bind to the internal palmitoylation pocket of TEAD, IAG933 acts as a direct surface disruptor [2]. It specifically targets and binds to interface 3 of the TEAD protein. By occupying this critical hydrophobic cavity, IAG933 competitively blocks the Ω-loop of YAP and TAZ from binding to TEAD. This physical disruption prevents the formation of the functional YAP/TAZ-TEAD transcriptional complex, thereby halting the downstream transcription of oncogenic target genes responsible for tumor growth, proliferation, and migration [1][2].
4. Structure-Activity Relationship (SAR)
The discovery and optimization of IAG933 represent a major breakthrough in structure-based rational drug design for difficult PPI targets. The development trajectory began with the study of linear YAP peptidomimetics [2]. Researchers utilized virtual screening to identify small molecules capable of mimicking chlorotryptophane—a residue in the linear YAP peptide that mimics the TAZ W43 residue, a known hotspot for TAZ-TEAD interaction [2].
This screening identified a dihydrobenzofuran core that could bind deeply into the hydrophobic cavity at TEAD interface 3 [2]. Subsequent medicinal chemistry efforts focused on optimizing this scaffold. The introduction of a 4-phenyl substituent to the benzofuran core (yielding "compound 3") boosted the binding affinity by two orders of magnitude. Further refinement led to highly potent derivatives (such as "compound 6") that exhibited single-digit nanomolar IC50 values and strongly inhibited YAP-TEAD complex formation as measured by TR-FRET assays [2]. By strategically targeting specific interaction hotspots rather than attempting to cover the entire PPI surface, the developers of IAG933 successfully improved the binding affinity of the initial hit by five orders of magnitude, yielding a highly effective non-peptide small molecule [2].
5. Current Limitations
Despite the clinical advancement of IAG933, targeting the YAP/TAZ-TEAD complex via direct surface disruption remains inherently difficult. The primary limitation lies in the biophysical nature of the target: the interaction interfaces between YAP/TAZ and TEAD are shallow, relatively flat, and span a massive surface area of approximately 1900 Ų [2]. There are very few deep binding pockets suitable for traditional small-molecule docking.
Because of these structural hurdles, strategically designing effective small-molecule PPIDs targeting TEAD interfaces 2 and 3 has been significantly more challenging compared to the development of allosteric inhibitors that target TEAD's central lipid pocket [2]. While IAG933 proves that interface 3 is druggable, the broader development of direct surface disruptors is still at an early stage, and achieving the necessary potency and pharmacokinetic properties for non-peptide molecules in this class remains a formidable obstacle in drug discovery [2].
6. Future Perspectives
The ongoing Phase I clinical trial of IAG933 (NCT04857372) is a critical milestone for the field of Hippo pathway therapeutics. The outcomes of this trial will be instrumental in validating TEAD as a safe and efficient cancer target, particularly for solid tumors driven by NF2/LATS mutations or YAP/TAZ fusions [1][2].
Furthermore, the successful design of IAG933 provides strong motivation for the continued development of surface TEAD inhibitors. It demonstrates that leveraging specific interaction hotspots can overcome the challenges of drugging large, flat PPIs [2]. Looking forward, validated PPIDs like IAG933 will not only serve as potential monotherapies or combination therapies to overcome drug resistance in oncology but will also be invaluable pharmacological tools to explore Hippo pathway biology in other diseases. Given the pathway's broad biological implications, there is growing interest in evaluating TEAD modulators for other indications, including fibrosis, heart disease, regenerative medicine, and neurodegenerative disorders [2].
