TEAD palmitoylation inhib News

|||||||||| Co-targeting EZH2 and TEAD elicits apoptosis through tumor-intrinsic innate immune signaling in Hippo pathway-mutated cancers (Section 18) - Mar 17, 2026 - Abstract #AACR2026AACR_4870;
Mechanistically, EZH2i/TEADi-treated cells exhibited heightened activation of tumor-intrinsic innate immune signaling which resulted in DNA damage and subsequent apoptosis. Taken together, we propose this novel combinatorial strategy as a potential approach to enhancing the anti-tumor efficacy of single agent TEAD targeting therapies in Hippo pathway altered tumors.

|||||||||| Undisclosed YAP/TAZ-TEAD inhibitor / Hanmi, AZD4625 / AstraZeneca, Lumakras (sotorasib) / Amgen
Comparative profiling of TEAD palmitoylation and YAP-TEAD protein-protein interaction inhibitors as combination agents with KRAS inhibitors (Room 31 - Upper Level - Convention Center) - Mar 17, 2026 - Abstract #AACR2026AACR_2433;
Therefore, targeting the YAP/TAZ-TEAD axis has the potential to inhibit tumor growth as a monotherapy or combination strategy across diverse indications...Additionally, the PPI re-sensitized KRASG12C-mutant NCI-H2122 cells resistant to AZD4625, a KRASG12C-selective inhibitor...In contrast to the in vitro results, CPI and PPIs drove equivalent regression of NCI-H2122 NSCLC xenografts when combined with the KRASG12C inhibitor sotorasib, followed by similar outgrowth once dosing was stopped...Collectively, these findings suggest that while differential activity was observed between TEAD CPI and PPIs in vitro, the two modalities drove similar therapeutic benefit in vivo when combined with KRAS inhibitors. Careful exploration of the long-term benefit of TEAD and KRAS inhibitor combinations is warranted due to the disconnect between in vitro and in vivo data.

|||||||||| VT3989 / Vivace Therap
P1/2 data, Journal: YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial. (Pubmed Central) - Dec 15, 2025
P1/2
VT3989 was recently awarded orphan drug designation and fast-track designation for the treatment of mesothelioma by the US Food and Drug Administration (FDA). ClinicalTrials.gov Identifier: NCT04665206 .

|||||||||| Undisclosed YAP/TAZ-TEAD inhibitor / Hanmi
Review, Journal: Targeting YAP/TAZ-TEAD and their protein-protein interaction for precision cancer therapy. (Pubmed Central) - Dec 3, 2025
Notably, several pioneer TEAD inhibitors and YAP/TAZ-TEAD protein-protein interaction inhibitors have progressed into clinical trials. This review dissects the structure and mechanistic details of YAP/TAZ-TEAD interactions and provides a comprehensive overview of recent advances in chemical compounds targeting YAP, TAZ, TEAD, and YAP/TAZ-TEAD PPI, highlighting the therapeutic potential of YAP/TAZ-TEAD axis as target for precision cancer therapy.

|||||||||| ethacrynic acid / Generic mfg.
Journal, IO biomarker: Discovery of repurposed ethacrynic acid and its derivatives as novel TEAD inhibitors. (Pubmed Central) - Dec 3, 2025
This review dissects the structure and mechanistic details of YAP/TAZ-TEAD interactions and provides a comprehensive overview of recent advances in chemical compounds targeting YAP, TAZ, TEAD, and YAP/TAZ-TEAD PPI, highlighting the therapeutic potential of YAP/TAZ-TEAD axis as target for precision cancer therapy. Representative compound EA-C15 covalently binds to the TEAD palmitoylation site, blocks palmitoylation and transcriptional activity, and inhibits NCI-H226

|||||||||| VT3989 / Vivace Therap
Safety and efficacy of first-in-class, YAP/TEAD inhibitor, VT3989 in refractory pleural and non-pleural mesothelioma: A phase I/II study (Hanover Auditorium - Hall 7.2c) - Jul 24, 2025 - Abstract #ESMO2025ESMO_1477;
P1/2
Conclusions VT3989 is well tolerated with promising antitumor activity in pts with refractory mesothelioma. Based on these data, a randomized phase 3 study is planned for further evaluation of VT3989 in mesothelioma.

|||||||||| Journal: Augmented Acyl-CoA Biosynthesis Promotes Resistance to TEAD Palmitoylation Site Inhibition. (Pubmed Central) - Apr 3, 2025
Here, we report that genetic augmentation of de novo coenzyme A biosynthesis desensitizes YAP-dependent cancer cells to treatment with TEAD inhibitors, an effect driven by increased levels of palmitoyl-CoA that outcompete drug for engagement of the lipid-binding pocket. This work uncovers a potential therapeutic resistance mechanism to TEAD palmitoylation site inhibition with implications for future combinatorial treatments in the clinic.

|||||||||| Journal: Pan-Transcriptional Enhanced Associated Domain Palmitoylation Pocket Covalent Inhibitor. (Pubmed Central) - Nov 14, 2024
Compound 1 was identified using a structure-based drug design approach, leveraging the molecular insights gained from the known TEAD palmitoylation site inhibitor, K-975. Optimization of the initial hit compound resulted in the development of compound 3, a covalent pan-TEAD inhibitor characterized by high potency and oral bioavailability.

|||||||||| Journal: Identification of resistance mechanisms to small-molecule inhibition of TEAD-regulated transcription. (Pubmed Central) - Sep 10, 2024
Consistent with this, combined inhibition of TEAD and the MAPK kinase MEK, synergistically blocks proliferation of multiple mesothelioma and lung cancer cell lines and more potently reduces the growth of patient-derived lung cancer xenografts in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies.

|||||||||| Undisclosed YAP/TAZ-TEAD inhibitor / Hanmi
Journal: Leveraging the Fragment Molecular Orbital and MM-GBSA Methods in Virtual Screening for the Discovery of Novel Non-Covalent Inhibitors Targeting the TEAD Lipid Binding Pocket. (Pubmed Central) - May 25, 2024
YAP/TAZ-TEAD facilitates the upregulation of multiple genes involved in evolutionary cell proliferation and survival...Subsequently, we optimized several analogs of BC-001 and found that the optimized compound BC-011 exhibited an IC50 of 72.43 nM. These findings can be used to design effective TEAD modulators with anticancer therapeutic implications.

|||||||||| Undisclosed YAP/TAZ-TEAD inhibitor / Hanmi
Journal: Allosteric Modulation of the YAP/TAZ-TEAD Interaction by Palmitoylation and Small-Molecule Inhibitors. (Pubmed Central) - Apr 12, 2024
Utilizing molecular dynamics simulations, our investigation not only provides detailed atomistic insight into the YAP/TAZ-TEAD dynamics but also unveils that the inhibitor studied influences the binding of YAP and TAZ to TEAD in distinct manners. This discovery has significant implications for the design and deployment of future molecular interventions targeting this interaction.

|||||||||| Discovery of a novel aryl ether small molecule inhibitor of the YAP1/TAZ-TEAD transcriptional complex (In-person; Room 356 (Ernest N. Morial Convention Center)) - Mar 12, 2024 - Abstract #ACSSp2024ACS_Sp_173;
Finally, MRK-A showed a favorable tolerability profile at predicted efficacious doses in mouse MTD studies and PK properties suitable for oral dosing in efficacy studies. In summary, we disclose the discovery of a novel and selective aryl ether series of YAP1/TAZ-TEAD transcriptional complex inhibitors with potential implications for treating Hippo-driven malignancies.

|||||||||| Undisclosed YAP/TAZ-TEAD inhibitor / Hanmi, VT3989 / Vivace Therap
Comparing TEAD palmitoylation inhibitors with differential TEAD selectivity in combination efficacy with targeted therapies and in renal safety (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_9410;
One of these compounds, VT3989, is being evaluated in an ongoing phase 1 clinical trial, where partial responses in mesothelioma patients have been demonstrated, showing for the first time that the Hippo pathway is druggable and that the Hippo pathway is now a validated target for cancer therapy...In 14-day/28-day rat studies, TEAD1-selective TEAD inhibitors also exhibited proteinuric nephropathy similar to that observed with pan-/multiple-TEAD inhibitors. Therefore, based on our findings, we can conclude that TEAD1-selective TEAD palmitoylation inhibitors can have similar on-target effect on kidneys as TEAD inhibitors with broader TEAD selectivity while having reduced anti-tumor efficacy and durability of response in combination with targeted therapies.

|||||||||| ETS-005 / Etern Biopharma
ETS-005, a highly selective TEAD4 palmitoylation inhibitor with potent anti-tumor activity and brain penetrating capability (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_9396;
Additionally, ETS-005 also exhibited profound synergistic effects in drug combination studies, offering broad opportunities combined with MAPK and RTK therapies. ETS-005 is currently in IND-enabling study and expected to enter Phase 1 in 2024.

|||||||||| Inhibition of pancreatic acinar ductal metaplasia by novel YAP/TAZ inhibitor, CV-4-26 (Section 31) - Mar 5, 2024 - Abstract #AACR2024AACR_7216;
However, less reduction in the collagens and extracellular matrix stiffness was observed in the ADM reversal treatments, corroborating our morphology and gene expression results. Our data suggest that combining CV-4-26 by ADM inhibition with standard of care therapies for PDAC may enhance the penetration of small molecules through the tumor's extracellular matrix.

|||||||||| ETS-006 / Etern Biopharma
Discovery of ETS-006, a highly potent YAP/TEADs PPI inhibitor with broad anti-tumor activity as a single agent (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_6885;
Notably, ETS-006 showed promising efficacy across multiple solid tumor types, including head and neck squamous cell carcinoma, osteosarcoma, and triple-negative breast cancer with urgent unmet clinical needs. In conclusion, ETS-006 is a highly potent and orally available YAP/TEADs PPI inhibitor with broad anti-tumor activity as a single agent.

|||||||||| ISM041-141b / Insilico Medicine
ISM6331, a novel and potent pan-TEAD inhibitor, exhibits strong anti-tumor activity in preclinical models of Hippo pathway-dysregulated cancers (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_4264;
In addition, ISM6331 showed excellent pharmacokinetic properties in multiple preclinical species and was well-tolerated in GLP-toxicity studies. In summary, ISM6331 has promising potential to treat Hippo pathway-dysregulated tumors as monotherapy as well as in combination with targeted therapies.

|||||||||| Identification of small molecule Pan-TEAD inhibitors disrupting YAP-TEAD protein-protein interaction and targeting gastric cancer cells (Section 52) - Mar 5, 2024 - Abstract #AACR2024AACR_2141;
In summary, ISM6331 has promising potential to treat Hippo pathway-dysregulated tumors as monotherapy as well as in combination with targeted therapies. Abstract is embargoed at this time.

|||||||||| Journal: Chloroacetamide fragment library screening identifies new scaffolds for covalent inhibition of the TEAD (Pubmed Central) - Sep 21, 2023
Binding pose hypotheses were generated by covalent docking revealing that the fragments and compounds engage lower, middle, and upper sub-sites of the palmitate pocket. Our fragments and compounds provide new scaffolds and starting points for the design of derivatives with improved inhibition potency of TEAD palmitoylation and binding to YAP1.

|||||||||| VT3989 / Vivace Therap
First-in-Human Phase 1 Trial of VT3989, a First-in-Class YAP/TEAD Inhibitor in Patients with Advanced Mesothelioma (Exhibit Hall) - Jul 25, 2023 - Abstract #IASLCWCLC2023IASLC_WCLC_2379;
This study provides the first clinical proof-of-concept for drugging the Hippo-YAP-TEAD pathway. RP2D optimization including further schedule evaluation and expansion are ongoing in mesothelioma patients evaluating different intermittent schedules.

|||||||||| Journal: Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma. (Pubmed Central) - Apr 21, 2023
In particular, successful use of TEAD palmitoylation inhibitors in a pre-clinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth.

|||||||||| VT3989 / Vivace Therap
First-in-class, first-in-human phase 1 trial of VT3989, an inhibitor of yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD), in patients (pts) with advanced solid tumors enriched for malignant mesothelioma and other tumors with neurofibromatosis 2 (NF2) mutations (W Hall A2-3 - Convention Center) - Mar 14, 2023 - Abstract #AACR2023AACR_3249;
VT3989 is safe and well tolerated with durable RECIST v1.1 antitumor responses in pts with advanced MM and NF2m cancers, providing the first early clinical proof-of-concept for effectively drugging the Hippo-YAP-TEAD pathway. RP2D optimization including further schedule evaluation and expansion are ongoing in pts with MM and NF2m tumors.

|||||||||| BPI-460372 / Betta Pharma
Discovery of BPI-460372, a potent and selective inhibitor of TEAD for the treatment of solid tumors harboring Hippo pathway aberrations (Section 18; Poster Board #1) - Mar 14, 2023 - Abstract #AACR2023AACR_2559;
In conclusion, BPI-460372 is a potent and selective TEAD palmitoylation inhibitor for the treatment of solid tumors harboring Hippo pathway aberrations. It is planned to enter Phase I clinical trial in China in early 2023.

|||||||||| Journal, IO biomarker: Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity. (Pubmed Central) - Dec 17, 2022
Consistent with the inhibitory effect of JM7 on YAP activity, it significantly impairs proliferation, colony-formation and migration of mesothelioma (NCI-H226), breast (MDA-MB-231) and ovarian (OVCAR-8) cancer cells that exhibit increased YAP activity. Collectively, these results establish JM7 as a novel lead compound for development of more potent inhibitors of TEAD palmitoylation for treating cancer.

|||||||||| Journal: Pharmacological blockade of TEAD-YAP reveals its therapeutic limitation in cancer cells. (Pubmed Central) - Nov 10, 2022
Consistently, combination of TEAD and AKT inhibitors exhibits strong synergy in inducing cancer cell death. Our work characterizes the therapeutic opportunities and limitations of TEAD palmitoylation inhibitors in cancers, and uncovers an intrinsic molecular mechanism, which confers potential therapeutic resistance.

|||||||||| SPR1 / Sporos Bio
A family of novel TEAD palmitoylation site inhibitors with exceptional pre-clinical anti-neoplastic activity as a monotherapy and in combination with MAPK inhibitors (Exhibition Hall) - Sep 3, 2022 - Abstract #AACRNCIEORTC2022AACR_NCI_EORTC_238;
TEAD inhibitors show exceptional anti-tumor effects in pre-clinical models in vivo, despite somewhat modest effects in vitro. We speculate that cell culture conditions (attachment, serum) minimize dependence on the Hippo pathway, and that TEAD inhibitors may have much broader utility than cell line-screening studies have suggested.

|||||||||| Journal: Discovering inhibitors of TEAD palmitate binding pocket through virtual screening and molecular dynamics simulation. (Pubmed Central) - Jun 8, 2022
In addition, we analyzed the binding modes of these small molecules to TEAD2, and confirmed the hot spot residues Cys380, Ser345, Tyr426, Phe428, Ile408, and Met379. AVAILABILITY OF DATA AND MATERIAL: Supplementary materials are available online.

|||||||||| Novel antagonists of TEAD palmitoylation inhibit the growth of Hippo-altered cancers in preclinical models (Section 22) - Mar 9, 2022 - Abstract #AACR2022AACR_6034;
In vivo models of Hippo pathway-altered xenografts showed consistent monotherapy activity, with dose-dependent and durable tumor regressions achieved at well-tolerated doses. Further characterization of these compounds as monotherapies and as part of rationally-designed combination regimens is ongoing.

|||||||||| Journal: Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription. (Pubmed Central) - Apr 28, 2021
Mechanistically, nuclear YAP/TAZ interact with Groucho/Transducin-Like Enhancer of Split (TLE) to block Wnt/T-cell factor (TCF)-mediated transcription, and dual inhibition of TEAD and Lats suppresses Wnt-uncoupled Myc upregulation and epithelial over-proliferation in Adenomatous polyposis coli (APC)-mutated intestine. Our studies highlight a pharmacological approach to inhibit TEAD palmitoylation and have important implications for targeting Wnt and Hippo signaling in human malignancies.

|||||||||| [VIRTUAL] Discovery of a covalent, cell-active pan-TEADs palmitoylation inhibitor () - Mar 28, 2021 - Abstract #ACSSp2021ACS-Sp_8033;
Besides, MYF-03-69 retarded the cell proliferation of YAP-activated NCI-H226 (NF2-deficient) and MSTO-211H (LATS1-PSEN1 fusion) mesothelioma cells by arresting cell cycle at G1 phase and exhibited excellent selectivity over normal mesothelium cells (MeT-5A) and YAP-insensitive NF2-intact mesothelioma cells (NCI-H2452). Our work highlights TEAD as an exploitable molecular vulnerability in mesothelioma and provides an efficient paradigm for combining covalent fragment screening with structure-based medicinal chemistry to develop new covalent prototype drugs.

|||||||||| SJP1901 / Samjin Pharma
[VIRTUAL] SJP1901, a small molecule inhibitor targeting hippo pathway by directly inhibiting TEAD palmitoylation in hippo pathway-dependent cancer () - Mar 11, 2021 - Abstract #AACR2021AACR_499;
SJP1901 showed outstanding anti-cancer effects through regulating hippo pathway-mediated target genes and lower toxicitiy in normal cells. In vivo efficacy study and research to expand the indications are currently ongoing.



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