TEAD inhibitors(TEA domain transcription factors inhibitors), WWTR1 inhibitors(WW domain containing transcription regulator 1 inhibitors), YAP1 inhibitors(Yes1 associated transcriptional regulator inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesRespiratory Diseases+ [1]

Active Indication

Advanced Malignant Solid NeoplasmBrain CancerMalignant Pleural Mesothelioma+ [1]

Inactive Indication-

Originator Organization

Novartis Pharmaceuticals Corp.

Active Organization

Novartis Pharmaceuticals Corp.

Novartis AG

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC27H26ClF2N3O4

InChIKeyHUVOYQMXUNTUAI-UHFFFAOYSA-N

CAS Registry2714434-21-4

Clinical Trials associated with IAG-933

NCT04857372

/ RecruitingPhase 1

An Open-label, Multi-center, Phase I Study of Oral IAG933 in Adult Patients With Advanced Mesothelioma and Other Solid Tumors

The purpose of this study is to characterize the safety and tolerability of IAG933 in patients with mesothelioma, NF2/LATS1/LATS2 mutated tumors and tumors with functional YAP/TAZ fusions and to identify the maximum tolerated dose and/or recommended dose.

Start Date21 Oct 2021

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with IAG-933

100 Translational Medicine associated with IAG-933

100 Patents (Medical) associated with IAG-933

Literatures (Medical) associated with IAG-933

01 Dec 2024·Journal of Cellular and Molecular Medicine

A Role for the Hippo/YAP1 Pathway in the Regulation of In Vitro Vasculogenic Mimicry in Glioblastoma Cells

Article

Author: Elimam, Rahil ; Annabi, Borhane ; Roy, Marie‐Eve ; Zgheib, Alain

ABSTRACTThe Hippo pathway plays a tumorigenic role in highly angiogenic glioblastoma (GBM), whereas little is known about clinically relevant Hippo pathway inhibitors' ability to target adaptive mechanisms involved in GBM chemoresistance. Their molecular impact was investigated here in vitro against an alternative process to tumour angiogenesis termed vasculogenic mimicry (VM) in GBM‐derived cell models. In silico analysis of the downstream Hippo signalling members YAP1, TAZ and TEAD1 transcript levels in low‐grade glioblastoma (LGG) and GBM tumour tissues was performed using GEPIA. TAZ transcript levels did not differ between the healthy and tumour tissues data analysed. In contrast, YAP1 transcript levels were elevated in GBM tissues, whereas TEAD1 levels were high in both LGG and GBM. 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. YAP1 gene and protein expression were induced upon VM, and its translocation to the nucleus was inhibited by the Hippo pathway inhibitors tested. 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.

01 Oct 2024·ChemMedChem

Direct Inhibition of the YAP : TEAD Interaction: An Unprecedented Drug Discovery Challenge

Review

Author: Chène, Patrick

AbstractThe Hippo pathway, which is key in organ morphogenesis, is frequently deregulated in cancer. The TEAD (TEA domain family member) transcription factors are the most distal elements of this pathway, and their activity is regulated by proteins such as YAP (Yes‐associated protein). The identification of inhibitors of the YAP : TEAD interaction is one approach to develop novel anticancer drugs: the first clinical candidate (IAG933) preventing the association between these two proteins by direct competition has just been reported. The discovery of this molecule was particularly challenging because the interface between these two proteins is large (~3500 Å2 buried in complex formation) and made up of distinct contact areas. The most critical of these involves an omega‐loop (Ω‐loop), a secondary structure element rarely found in protein‐protein interactions. This review summarizes how the knowledge gained from structure‐function studies of the interaction between the Ω‐loop of YAP and TEAD was used to devise the strategy to identify potent low‐molecular weight compounds that show a pronounced anti‐tumor effect.

Nature Cancer

Author Correction: Direct and selective pharmacological disruption of the YAP–TEAD interface by IAG933 inhibits Hippo-dependent and RAS–MAPK-altered cancers

Author: Martin, Typhaine ; Sellner, Holger ; Chapeau, Emilie A ; Mesrouze, Yannick ; Galli, Giorgio G ; Brachmann, Saskia M ; Barbosa, Ines A M ; Bauer, Daniel ; Baltschukat, Sabrina ; Hofmann, Francesco ; Furet, Pascal ; Hueber, Andreas ; Sterker, Dario ; Mourikis, Thanos P ; Delaunay, Clara ; Estadieu, Claire ; Soldermann, Nicolas ; Wartmann, Markus ; Romanet, Vincent ; Stamm, Christelle ; Sansregret, Laurent ; Mandon, Emeline ; Schmelzle, Tobias ; Tordella, Luca ; Jaaks, Patricia ; Jiménez Núñez, Eloísa ; Chène, Patrick ; Kodack, David P ; Faris, Jason E ; Scheufler, Clemens ; Harlfinger, Stefanie

100 Deals associated with IAG-933

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Malignant Pleural Mesothelioma	Phase 1	Netherlands	Novartis Pharmaceuticals Corp.	21 Oct 2021
Malignant Pleural Mesothelioma	Phase 1	Japan	Novartis Pharmaceuticals Corp.	21 Oct 2021
Malignant Pleural Mesothelioma	Phase 1	Italy	Novartis Pharmaceuticals Corp.	21 Oct 2021
Malignant Pleural Mesothelioma	Phase 1	Canada	Novartis Pharmaceuticals Corp.	21 Oct 2021
Malignant Pleural Mesothelioma	Phase 1	France	Novartis Pharmaceuticals Corp.	21 Oct 2021
Malignant Pleural Mesothelioma	Phase 1	United Kingdom	Novartis Pharmaceuticals Corp.	21 Oct 2021
Malignant Pleural Mesothelioma	Phase 1	Spain	Novartis Pharmaceuticals Corp.	21 Oct 2021
Malignant Pleural Mesothelioma	Phase 1	Switzerland	Novartis Pharmaceuticals Corp.	21 Oct 2021
Malignant Pleural Mesothelioma	Phase 1	United States	Novartis Pharmaceuticals Corp.	21 Oct 2021
Malignant Pleural Mesothelioma	Phase 1	Australia	Novartis Pharmaceuticals Corp.	21 Oct 2021

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