Author: Zhao, Yujun ; Yan, Ziqin ; Xu, Lan ; Wang, Chenxu ; Lu, Yuhang ; Lou, Jianfeng ; Lyu, Xilin ; Meng, Linghua ; Huang, He ; Sun, Jiaqi ; Wang, Xiancheng

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.

25 Feb 2025·Chemistry – A European Journal

Light‐Dependent Amide or Thioamide Formation of Acylsilanes with Amines using Elemental Sulfur

Article

Author: Wang, Shaohong ; Li, Jing ; Ma, Pengchen ; Houk, Kendall N. ; Lear, Martin J. ; Xu, Silong ; Li, Yuanhang ; Ye, Haiting

AbstractDue to the diverse chemical and physical properties of functional groups, mild and controllable ligation methods are often required to construct complex drugs and functional materials. To make diverse sets of products with tunable physicochemical properties, it is also useful to employ complimentary ligation methods that adopt the same starting materials. Here, we disclose the efficient and modular synthesis of amides or thioamides through the chemical ligation of acylsilanes with amines, simply by turning a light on or off. This method is fast, mild, high‐yielding and displays excellent functional‐group tolerance. The versatility of these reactions is highlighted by their ability to perform post‐synthetic modifications on a variety of marketed medications, peptides, natural substances, and compounds with biological activity. In‐depth computational and experimental studies clarified the photo‐dependent umpolung of reactivity of acylsilanes, namely: photoexcitation leads to nucleophilic O‐silyl carbenes that react with S8 to form O‐silyl thionoesters and eventually amides. In contrast, acylsilanes react as electrophiles with amines thermally in the dark, with C→O silyl transfer, prior to reacting with S8 to form thioamides. These mechanistic details are expected to guide the development of similar coupling reactions.

02 Jan 2025·Chemistry – An Asian Journal

Diastereoselective Synthesis of Highly Functionalized γ‐Lactams via Ugi Reaction/Michael Addition

Article

Author: Vidal, Herika D. A. ; Ellena, Javier ; Santiago, Pedro H. O. ; Januário, Marcelo A. P. ; Nunes, Paulo S. G. ; Martinez, Alice K. A. ; Corrêa, Arlene G.

AbstractThe γ‐lactam ring is a prominent feature in medicinal chemistry, and its synthesis has garnered significant interest due to its valuable properties. Among the γ‐lactams, 2‐oxopyrrolidine‐3‐carbonitrile derivatives stand out as versatile synthons that can be readily transformed into a variety of other functional groups. In this work, we successfully synthesized highly functionalized 3‐cyano‐2‐pyrrolidinones with moderate to good overall yields using the Ugi reaction followed by intramolecular Michael addition. The process demonstrated excellent diastereoselectivity and showed good tolerance to a range of isonitriles and carbonyl compounds.

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