IAG933

In this study, we investigated the anti-inflammatory and anti-invasive properties of 1,3,6-tri-O-galloyl-α-D-glucose (αTGG), the α-anomer of βTGG from Terminalia chebula, in comparison with pharmacological Hippo pathway inhibitors IAG933, VT107, and GNE7883...Importantly, αTGG and VT107 also significantly attenuated ConA-induced activation of proMMP-2 to MMP-2 and reduced the expression of multiple pro-inflammatory mediators, including COX2, CCL22, CCR2, CCR4, CXCL10, CXCL12, CXCR1, FASLG, IFNG, IL13, and IL17A. These findings underscore the dual anti-inflammatory and anti-invasive actions of αTGG, positioning it as a promising candidate for targeting inflammation-driven GBM progression through modulation of Hippo pathway activity.

P1, N=137, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

They demonstrated efficacy against colorectal cancer cells resistant to the KRAS-dependent clinical candidate IAG933 and confirmed the ability to inhibit TEAD4 target genes expression. Bioinformatic metabolic pathway analysis further differentiated the mechanism of action of the 6a analogs from verteporfin, a known indirect modulator of the Y:T complex. These findings establish the pyrazolo-piperidinone class as novel Y:T disruptors and provide insights into their metabolic impact on downstream effectors, offering a valuable framework for future hit-to-lead optimization and mechanism of action studies.

Preclinical and clinical investigations highlight the efficacy of diverse Hippo/YAP-targeted interventions, with recent clinical trials (e.g., VT3989, IK-930, IAG933, ION537) underscoring the translational promise of this pathway. Integrating cutting-edge insights into its regulatory networks and clinical targeting offers novel perspectives for precision oncology. By bridging fundamental discoveries with translational applications, this review establishes Hippo/YAP as a compelling therapeutic target and provides a theoretical foundation for developing innovative CRC therapies.

All three Hippo pathway inhibitors tested, GNE7883, VT107 and IAG933 effectively inhibited U87 and U251 cell migration and in vitro VM as assessed on Cultrex matrix...SiRNA-mediated transient silencing of YAP1 repressed cell migration, VM formation and CTGF and Cyr61 transcription. In conclusion, targeting of VM using Hippo pathway inhibitors could help circumvent GBM chemoresistance and effectively complement other brain cancer treatments.

P1, N=156, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2026 --> Sep 2026 | Trial primary completion date: Jan 2026 --> Sep 2026

P1, N=156, Recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2025 --> Jan 2026 | Trial primary completion date: Oct 2025 --> Jan 2026

Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.

P1, N=156, Recruiting, Novartis Pharmaceuticals | Trial completion date: May 2025 --> Oct 2025 | Trial primary completion date: May 2025 --> Oct 2025

P1, N=156, Recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2024 --> May 2025 | Trial primary completion date: Sep 2024 --> May 2025

Here we report the identification of IAG933, the first molecule able to potently and directly disrupt the YAP/TAZ-TEADs PPI with suitable properties to enter in clinical trial. Moreover, we provide evidence for combination benefits of IAG933 with several MAPK/KRAS inhibitors, both in vitro and in vivo, in non-Hippo altered models including lung, pancreatic and colorectal cancer. Overall, our results provide a rationale of progressing IAG933 as a monotherapy in patients with Hippo-mutated cancers, and as a combination partner in MAPK-dependent cancers, with the potential to treat patient populations of high unmet medical need.