Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo
Yuhang Lu1,2, Ziqin Yan1, Jiaqi Sun3,2
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China.
Abstract:
Genetic mutations in components of the Hippo pathway frequently lead to the aberrant activation of TEADs, which is often associated with cancer. Consequently, TEADs have been actively pursued as therapeutic targets for diseases driven by TEAD overactivation. In this study, we report two series of TEAD PROTACs based on CRBN binders and VHL binders. Both series yielded potent TEAD degraders, including 19 and 40 (H122), which induced TEAD1 degradation with DC50 < 10 nM. Mechanistic studies demonstrated that the degradation of TEAD1 induced by 40 relied on CRBN binding, TEAD1 binding, E3 ligase activity, and a functional proteasome. RNA-seq analyses indicated that 40 significantly downregulated the expression of Myc target genes, as highlighted by GSEA analysis. More importantly, 40 exhibited robust antitumor efficacy in the MSTO-211H mouse xenograft model. Collectively, our results suggest that TEAD PROTACs have therapeutic potential for the treatment of cancers associated with TEAD overactivation.
Insights
Researchers developed novel TEAD PROTACs (proteolysis-targeting chimeras) to target TEAD transcription factors implicated in cancer. Compound 40 effectively degraded TEAD1 and demonstrated significant antitumor activity in preclinical models, suggesting therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Hippo pathway mutations aberrantly activate TEAD transcription factors, driving cancer development.
- TEADs are recognized as promising therapeutic targets for cancers associated with their overactivation.
Purpose of the Study:
- To design and evaluate novel TEAD-targeted Proteolysis-Targeting Chimeras (PROTACs) for cancer therapy.
- To investigate the degradation mechanism and antitumor efficacy of developed TEAD PROTACs.
Main Methods:
- Synthesis of two series of TEAD PROTACs utilizing CRBN and VHL binders.
- Assessment of TEAD1 degradation potency (DC50) and mechanistic studies involving CRBN binding, TEAD1 binding, E3 ligase activity, and proteasome function.
- RNA-sequencing and Gene Set Enrichment Analysis (GSEA) to analyze gene expression changes.
- Evaluation of antitumor efficacy in a MSTO-211H mouse xenograft model.
Main Results:
- Identification of potent TEAD degraders, including compound 40 (H122), with TEAD1 degradation DC50 < 10 nM.
- Mechanistic studies confirmed that compound 40-induced TEAD1 degradation requires CRBN binding, TEAD1 binding, E3 ligase activity, and a functional proteasome.
- Compound 40 significantly downregulated Myc target genes, as shown by RNA-seq and GSEA.
- Compound 40 demonstrated robust antitumor efficacy in a preclinical mouse xenograft model.
Conclusions:
- TEAD PROTACs, exemplified by compound 40, are effective in degrading TEAD1 and exhibit significant antitumor activity.
- These findings highlight the therapeutic potential of TEAD PROTACs for treating cancers driven by TEAD overactivation.
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