Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity

Gridnev, Artem; Maity, Subhajit; Misra, Jyoti R.

doi:10.3389/fonc.2022.1021823

Cited by 12 publications

(10 citation statements)

References 53 publications

(63 reference statements)

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“…In general, the NCI-H226 cell line is recognized as a well-characterized YAP-dependent mesothelioma cell line, 51, 52 and among the three YAP-TEAD inhibitors currently undergoing clinical trials, all of them are intended for the treatment of mesothelioma (Clinical trial information: NCT05228015, NCT04857372, NCT04665206). In order to gain initial insights into the cellular effects of our designed YAP degraders, we evaluated the potency of each synthesized compound in terms of cell growth inhibition using this NCI-H226 cell line here.…”

Section: Resultsmentioning

confidence: 99%

Exploring Degradation of Intrinsically Disordered Protein YAP induced by PROTACs

Zhou,

Sun,

et al. 2023

Preprint

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Yes-associated protein (YAP), a potent oncogene and a key player in the Hippo tumor suppression pathway, has long been considered challenging to target due to its partially intrinsically disordered nature. However, recent advances in High-throughput Screening (HTS) have led to the discovery of a few YAP binders. Building upon this progress, a novel approach utilizing Proteolysis-Targeting Chimera (PROTAC) technology was employed to design and synthesize a series of YAP degraders. Here, our degraders were created by linking NSC682769, a previously reported YAP binder, with either VHL ligand 2 or pomalidomide using various linkers of different lengths and types. The most promising degrader YZ-6 recruits the E3 ligase VHL, inducing rapid and sustained YAP degradation leading to suppression of YAP/TEAD-led transcription in both YAP-dependent NCI-H226 and Huh7 cancer cell lines. In addition to its degradation capabilities, YZ-6 also exhibited potent antiproliferative activity in both cell lines. Importantly, YZ-6 efficiently suppresses tumor development in the Huh7 xenograft mouse model without adverse effects on the mice. These findings highlight the potential of PROTAC-mediated degradation as a viable strategy for reducing oncogenic YAP levels and attenuating downstream signaling in cancer cells. Moreover, the development of PROTACs based on NSC672869 holds promise for treating YAP-driven malignancies.

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Section: Resultsmentioning

confidence: 99%

Exploring Degradation of Intrinsically Disordered Protein YAP induced by PROTACs

Zhou,

Sun,

et al. 2023

Preprint

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“…However, YAP and TAZ are not therapeutically amenable due to their intrinsically disordered structure. 7 Because YAP and TAZ must associate with TEAD to exert their oncogenic activity, disrupting the YAP/TAZ-TEAD interaction offers an indirect means of inhibiting their activity. Additionally, the binding interfaces between YAP/TAZ and TEAD are wide, shallow, and solvent-exposed, making them unsuitable for direct therapeutic targeting.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Additionally, the binding interfaces between YAP/TAZ and TEAD are wide, shallow, and solvent-exposed, making them unsuitable for direct therapeutic targeting. 7 Consequently, alternative strategies have been devised to allosterically disrupt this interaction.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Hence, YAP/TAZ provides an attractive target for therapeutic intervention in cancer treatment. However, YAP and TAZ are not therapeutically amenable due to their intrinsically disordered structure . Because YAP and TAZ must associate with TEAD to exert their oncogenic activity, disrupting the YAP/TAZ-TEAD interaction offers an indirect means of inhibiting their activity.…”

Section: Introductionmentioning

confidence: 99%

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Allosteric Modulation of the YAP/TAZ-TEAD Interaction by Palmitoylation and Small-Molecule Inhibitors

Mills,

Misra,

Torabifard

2024

J. Phys. Chem. B

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The Hippo signaling pathway is a highly conserved signaling network that plays a central role in regulating cellular growth, proliferation, and organ size. This pathway consists of a kinase cascade that integrates various upstream signals to control the activation or inactivation of YAP/TAZ proteins. Phosphorylated YAP/TAZ is sequestered in the cytoplasm; however, when the Hippo pathway is deactivated, it translocates into the nucleus, where it associates with TEAD transcription factors. This partnership is instrumental in regulating the transcription of progrowth and antiapoptotic genes. Thus, in many cancers, aberrantly hyperactivated YAP/TAZ promotes oncogenesis by contributing to cancer cell proliferation, metastasis, and therapy resistance. Because YAP and TAZ exert their oncogenic effects by binding with TEAD, it is critical to understand this key interaction to develop cancer therapeutics. Previous research has indicated that TEAD undergoes autopalmitoylation at a conserved cysteine, and small molecules that inhibit TEAD palmitoylation disrupt effective YAP/TAZ binding. However, how exactly palmitoylation contributes to YAP/TAZ-TEAD interactions and how the TEAD palmitoylation inhibitors disrupt this interaction remains unknown. 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.

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“…However, YAP and TAZ are not therapeutically amenable, due to their intrinsically disordered structure. 7 Because YAP and TAZ must associate with TEAD to exert their oncogenic activity, disrupting the YAP/TAZ-TEAD interaction offers an indirect means to inhibit their activity. Additionally, the binding interfaces between YAP/TAZ and TEAD are wide, shallow, and solvent-exposed, making them unsuitable for direct therapeutic targeting.…”

Section: Introductionmentioning

confidence: 99%

Allosteric Modulation of YAP/TAZ-TEAD Interaction by Palmitoylation and Small Molecule Inhibitors

Mills,

Misra,

Torabifard

2023

Preprint

View full text Add to dashboard Cite

The Hippo signaling pathway is a highly conserved signaling network that plays a central role in regulating cellular growth, proliferation, and organ size. This pathway consists of a kinase cascade that integrates various upstream signals to control the activation or inactivation of YAP/TAZ proteins. Phosphorylated YAP/TAZ is sequestered in the cytoplasm; however, when the Hippo pathway is deactivated, they translocate into the nucleus, where they associate with TEAD transcription factors. This partnership is instrumental in regulating the transcription of pro-growth and anti-apoptotic genes. Thus, in many cancers, aberrantly hyperactivated YAP/TAZ promotes oncogenesis by contributing to cancer cell proliferation, metastasis, and therapy resistance. Because YAP and TAZ exert their oncogenic effects by binding with TEAD, it is critical to understand this key interaction to develop cancer therapeutics. Previous research has indicated that TEAD undergoes an auto-palmitoylation at a conserved cysteine, and small molecules that inhibit TEAD palmitoylation disrupt effective YAP/TAZ binding. However, how exactly palmitoylation contributes to YAP/TAZ-TEAD interactions and how the TEAD palmitoylation inhibitors disrupt this interaction remains unknown. Utilizing molecular dynamics simulations, our investigation not only provides a detailed atomistic insight into the YAP/TAZ-TEAD dynamics but also unveils that the inhibitor studied influences YAP and TAZ binding to TEAD in distinct manners. This discovery holds significant implications for the design and deployment of future molecular interventions targeting this interaction.

show abstract

Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity

Cited by 12 publications

References 53 publications

Exploring Degradation of Intrinsically Disordered Protein YAP induced by PROTACs

Exploring Degradation of Intrinsically Disordered Protein YAP induced by PROTACs

Allosteric Modulation of the YAP/TAZ-TEAD Interaction by Palmitoylation and Small-Molecule Inhibitors

Allosteric Modulation of YAP/TAZ-TEAD Interaction by Palmitoylation and Small Molecule Inhibitors

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