IAG933, a novel small-molecule inhibitor targeting the YAP/TAZ-TEAD protein-protein interaction (PPI), has demonstrated promising preclinical activity and tolerability in various cancer models. This first-in-class direct disruptor of the YAP/TAZ-TEAD interface has shown significant tumor regression in Hippo-driven mesothelioma xenografts and efficacy in combination with RTK, KRAS-mutant selective, and MAPK inhibitors in lung, pancreatic, and colorectal cancer models. Clinical evaluation of IAG933 is currently underway (NCT04857372).
The four paralogs of the TEA/ATSS domain transcription factor (TEAD1-TEAD4) are the most distal effectors of the Hippo signaling pathway, which regulates cell growth, tissue homeostasis, and embryonic development. Inhibition of the Hippo pathway and subsequent increased TEAD transcriptional activity promote tumorigenesis or resistance to therapies in a wide variety of cancers, including malignant mesothelioma, non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC).
Mechanism of Action
IAG933 directly prevents complex formation between YAP/TAZ and TEADs by competition at the binding site. The cocrystal structure of IAG933 with TEAD3 (2 Å) shows a combination of polar and hydrophobic interactions with its Ω-loop pocket, recognized as the interface of the PPI with YAP and TAZ. Surface plasmon resonance showed comparable binding of IAG933-related YTPs across all four paralogs. IAG933 treatment for 24 hours almost completely inhibited the expression of direct TEAD target genes CCN1, ANKRD1 and CCN2 in both MSTO-211H cells and another Hippo-altered mesothelioma line NCI-H226 (NF2 loss of function), with half-maximal inhibitory concentration (IC50) values between 11 and 26 nM.
Preclinical Efficacy
In vivo studies demonstrated that IAG933 effectively inhibits TEAD target gene expression in MSTO-211H subcutaneous tumors after single-dose administration. The in vivo blood IC50 for target gene inhibition was 64 nM, slightly higher than the in vitro IC50 of 11–26 nM for MSTO-211H cells. Under extended daily dosing (2–4 weeks) of mouse models bearing orthotopic or subcutaneous MSTO-211H xenografts, IAG933 or YTP-75 antitumor effects were comparable and accompanied by significant dose-dependent responses that ranged from near stasis to profound tumor regression.
Combination Strategies
IAG933 has shown synergistic effects when combined with other targeted therapies. For instance, the combination of IAG933 with the KRAS G12C inhibitor JDQ443 displayed strong combination benefit in a panel of KRAS G12C-mutated NSCLC and CRC cell lines. In vivo, upfront addition of IAG933 deepened responses to JDQ443 in NCI-H2122 NSCLC xenografts. Similarly, IAG933 plus osimertinib showed enhanced antitumor benefit, leading to rapid regression in the EGFR-mutated NCI-H1975 CDX model of NSCLC. Furthermore, IAG933 plus the MET inhibitor capmatinib induced profound tumor shrinkage in the EBC-1 MET-amplified CDX model of lung cancer.
Clinical Development
Based on these promising preclinical findings, IAG933 is currently under clinical evaluation in a first-in-human study (NCT04857372) for patients with Hippo-driven tumors. The ongoing trials will provide critical insights into the safety, pharmacokinetics, and potential efficacy of IAG933 as a novel therapeutic strategy for various solid tumors.
