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

Neoplasms

Active Indication

MesotheliomaSolid tumorNeoplasms

Inactive Indication-

Originator Organization

Novartis Pharmaceuticals Corp.

Active Organization

Novartis Pharmaceuticals Corp.

Novartis AG

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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 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

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

Article

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

AbstractThe YAP–TEAD protein–protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP–TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP–TEAD protein–protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. 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.

Pharmaceuticals

Leveraging Hot Spots of TEAD–Coregulator Interactions in the Design of Direct Small Molecule Protein-Protein Interaction Disruptors Targeting Hippo Pathway Signaling

Review

Author: Pobbati, Ajaybabu V ; Zhao, Bin ; Rubin, Brian P ; Stauffer, Shaun

The Hippo signaling pathway is a highly conserved pathway that plays important roles in the regulation of cell proliferation and apoptosis. Transcription factors TEAD1-4 and transcriptional coregulators YAP/TAZ are the downstream effectors of the Hippo pathway and can modulate Hippo biology. Dysregulation of this pathway is implicated in tumorigenesis and acquired resistance to therapies. The emerging importance of YAP/TAZ-TEAD interaction in cancer development makes it a potential therapeutic target. In the past decade, disrupting YAP/TAZ-TEAD interaction as an effective approach for cancer treatment has achieved great progress. This approach followed a trajectory wherein peptidomimetic YAP–TEAD protein-protein interaction disruptors (PPIDs) were first designed, followed by the discovery of allosteric small molecule PPIDs, and currently, the development of direct small molecule PPIDs. YAP and TEAD form three interaction interfaces. Interfaces 2 and 3 are amenable for direct PPID design. One direct YAP–TEAD PPID (IAG933) that targets interface 3 has entered a clinical trial in 2021. However, in general, strategically designing effective small molecules PPIDs targeting TEAD interfaces 2 and 3 has been challenging compared with allosteric inhibitor development. This review focuses on the development of direct surface disruptors and discusses the challenges and opportunities for developing potent YAP/TAZ-TEAD inhibitors for the treatment of cancer.

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
Mesothelioma	Phase 1	CH	Novartis Pharmaceuticals Corp.	21 Oct 2021
Mesothelioma	Phase 1	ES	Novartis Pharmaceuticals Corp.	21 Oct 2021
Mesothelioma	Phase 1	IT	Novartis Pharmaceuticals Corp.	21 Oct 2021
Mesothelioma	Phase 1	JP	Novartis Pharmaceuticals Corp.	21 Oct 2021
Mesothelioma	Phase 1	FR	Novartis Pharmaceuticals Corp.	21 Oct 2021
Mesothelioma	Phase 1	GB	Novartis Pharmaceuticals Corp.	21 Oct 2021
Mesothelioma	Phase 1	AU	Novartis Pharmaceuticals Corp.	21 Oct 2021
Mesothelioma	Phase 1	NL	Novartis Pharmaceuticals Corp.	21 Oct 2021
Mesothelioma	Phase 1	US	Novartis Pharmaceuticals Corp.	21 Oct 2021
Solid tumor	Phase 1	AU	Novartis Pharmaceuticals Corp.	12 Oct 2021

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