Abstract: The Hippo signaling pathway and its downstream effectors, YAP/TAZ and TEAD transcription factors, play a critical role in tumorigenesis and cancer progression. Dysregulation of this pathway is frequently observed in various cancers, including malignant mesothelioma. IAG933 is a novel, direct small-molecule protein-protein interaction disruptor (PPID) that selectively targets the YAP/TAZ-TEAD complex. By binding to the interface 3 region on the surface of TEAD, IAG933 effectively blocks YAP/TAZ transcriptional output. It is currently being evaluated in a Phase I clinical trial for malignant mesothelioma and other solid tumors harboring NF2/LATS1/2 mutations or YAP/TAZ fusions. The development of IAG933 represents a significant breakthrough in targeting broad, shallow protein-protein interfaces and provides a promising therapeutic strategy for Hippo-dependent cancers.
1. Introduction
The evolutionarily conserved Hippo signaling pathway plays a pivotal role in regulating cell proliferation, apoptosis, and tissue homeostasis [2]. Dysregulation of this pathway is strongly associated with the development and progression of various human malignancies, including malignant mesothelioma [1][2]. The core downstream mechanism involves the unphosphorylated transcriptional coregulators YAP (Yes-associated protein) and TAZ translocating into the nucleus, where they bind to TEAD (TEA/ATTS domain) transcription factors to drive the expression of oncogenic target genes [1][2].
Given the reliance of these cancers on the YAP/TAZ-TEAD interaction, disrupting this complex has emerged as an attractive therapeutic strategy [2]. While early efforts focused on peptidomimetics and allosteric inhibitors that bind to TEAD's central palmitoylation pocket, recent advancements have led to the development of direct small-molecule protein-protein interaction disruptors (PPIDs) [2]. IAG933, developed by Novartis, is a first-in-class direct surface disruptor of the YAP-TEAD interaction that entered clinical testing in 2021, marking a major milestone in targeting Hippo pathway signaling for cancer therapy [2].
2. Pharmacological Activity
IAG933 is a highly potent and selective small-molecule inhibitor designed to disrupt YAP/TAZ-TEAD protein-protein interactions [1]. In preclinical evaluations, compounds from the IAG933 scaffold series demonstrated tight biochemical potency, achieving single-digit nanomolar IC50 values for the inhibition of YAP-TEAD complex formation as measured by TR-FRET assays [2]. This biochemical activity translated into very strong inhibition of YAP-TEAD-dependent gene expression in cellular models, such as NCI-H2052 cells [2].
Clinically, IAG933 is currently being evaluated in a Phase I trial (NCT04857372) [1]. The trial specifically targets patients with malignant mesothelioma and other advanced solid tumors that feature Hippo pathway alterations, such as NF2/LATS1/2 mutations or YAP/TAZ fusions [1]. The outcomes of this ongoing trial will be critical in validating the pharmacological efficacy and safety of directly targeting TEAD in these specific cancer populations [2].
3. Molecular Mechanism of Action
The molecular mechanism of IAG933 distinguishes it from other TEAD inhibitors (such as VT3989 and IK-930) that act allosterically by binding to the central palmitoylation pocket of TEAD [1][2]. Instead, IAG933 functions as a direct surface disruptor [2]. YAP and TEAD form three primary interaction interfaces, with interfaces 2 and 3 being the most amenable for direct PPID design [2]. IAG933 specifically targets interface 3, which corresponds to the twisted-coil region or omega-loop (Ω-loop) of the YAP/TAZ-TEAD complex [2].
By binding deeply into the hydrophobic cavity at interface 3 of TEAD, IAG933 directly competes with and blocks the binding of YAP and TAZ [2]. This selective disruption of the YAP-TEAD protein-protein binding interface prevents the formation of the functional transcriptional complex, thereby suppressing YAP/TAZ transcriptional output and halting the expression of downstream oncogenic genes responsible for tumor growth and proliferation [1][2].
4. Structure-Activity Relationship (SAR)
The discovery and optimization of the IAG933 scaffold utilized a structure-based rational drug design approach, originating from the groundwork laid by linear YAP peptidomimetics [2]. Researchers initially used a virtual screen to identify small-molecule mimics of chlorotryptophan—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 interface 3 of TEAD [2].
Medicinal chemistry efforts were then applied to optimize this initial hit. The introduction of a 4-phenyl substituent to the benzofuran core boosted the binding affinity by two orders of magnitude [2]. Further structural refinement led to an optimized compound that improved the binding affinity of the initial hit by a total of five orders of magnitude, achieving a single-digit nanomolar IC50 value [2]. This progression highlights how taking advantage of specific interaction hotspots can effectively reduce the need for a small molecule to occupy the entirety of a large, flat protein-protein interface [2]. While the exact chemical structure of IAG933 remains undisclosed, a 2021 patent by Novartis describes this highly potent YAP-TEAD inhibitor scaffold [2].
5. Current Limitations
The primary limitation in the development of drugs like IAG933 lies in the inherent difficulty of targeting protein-protein interactions. Strategically designing effective small-molecule PPIDs that target TEAD interfaces 2 and 3 has proven to be significantly more challenging than developing allosteric inhibitors [2]. The interaction interfaces between YAP/TAZ and TEAD are broad, shallow, and span a large surface area (approximately 1900 Ų), providing very few deep binding pockets that are traditionally required for small-molecule binding [2]. Furthermore, the specific chemical structure of IAG933 has not been publicly disclosed in the provided literature, limiting broader structural analysis by the scientific community [2].
6. Future Perspectives
The advancement of IAG933 into clinical trials represents a major breakthrough in the field of Hippo pathway therapeutics [2]. The outcomes of the ongoing Phase I trial (NCT04857372) will be crucial in validating TEAD as a safe and efficient target for cancer therapy, particularly for malignant mesothelioma and other tumors driven by NF2 or LATS mutations [1][2].
Moreover, the successful design of IAG933 demonstrates the feasibility of creating non-peptide small molecules that can effectively target broad and shallow protein-protein interfaces [2]. This achievement provides strong motivation for the continued development of surface TEAD inhibitors. Future research may also explore the utility of TEAD modulators in other indications where the Hippo pathway is implicated, such as fibrotic diseases, heart disease, and regenerative medicine [2].
