Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors

“…Cell Proliferation assay was conducted as previously described . EGFR L858R , EGFR L858R/C775S , and EGFR L858R/C797S Ba/F3 cells were seeded at the density of 1000 cells per well in 384-well plates (Corning, #3570).…”

Section: Methodsmentioning

confidence: 99%

ZNL0325, a Pyrazolopyrimidine-Based Covalent Probe, Demonstrates an Alternative Binding Mode for Kinases

Li,

Lu,

Beyett

et al. 2024

J. Med. Chem.

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The pyrazolopyrimidine (PP) heterocycle is a versatile and widely deployed core scaffold for the development of kinase inhibitors. Typically, a 4-amino-substituted pyrazolopyrimidine binds in the ATP-binding pocket in a conformation analogous to the 6-aminopurine of ATP. Here, we report the discovery of ZNL0325 which exhibits a flipped binding mode where the C3 position is oriented toward the ribose binding pocket. ZNL0325 and its analogues feature an acrylamide side chain at the C3 position which is capable of forming a covalent bond with multiple kinases that possess a cysteine at the αD-1 position including BTK, EGFR, BLK, and JAK3. These findings suggest that the ability to form a covalent bond can override the preferred noncovalent binding conformation of the heterocyclic core and provides an opportunity to create structurally distinct covalent kinase inhibitors.

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“…Multiple good binders that look like L-shaped compounds bind well into the TEAD palmitoylation pocket. However, recent Y-shaped designs strongly occupy a large hydrophobic pocket and potentially enhance the potency [41]. Multiple covalent and non-covalent TEAD binders with good potency are neither L-shaped nor Y-shaped compounds (Figure 2).…”

Section: Targeting Tead-driven Yap/taz Signaling and Yap Amplificatio...mentioning

confidence: 99%

Hippo Signaling at the Hallmarks of Cancer and Drug Resistance

Kumar,

Hong

2024

Cells

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Originally identified in Drosophila melanogaster in 1995, the Hippo signaling pathway plays a pivotal role in organ size control and tumor suppression by inhibiting proliferation and promoting apoptosis. Large tumor suppressors 1 and 2 (LATS1/2) directly phosphorylate the Yki orthologs YAP (yes-associated protein) and its paralog TAZ (also known as WW domain-containing transcription regulator 1 [WWTR1]), thereby inhibiting their nuclear localization and pairing with transcriptional coactivators TEAD1-4. Earnest efforts from many research laboratories have established the role of mis-regulated Hippo signaling in tumorigenesis, epithelial mesenchymal transition (EMT), oncogenic stemness, and, more recently, development of drug resistances. Hippo signaling components at the heart of oncogenic adaptations fuel the development of drug resistance in many cancers for targeted therapies including KRAS and EGFR mutants. The first U.S. food and drug administration (US FDA) approval of the imatinib tyrosine kinase inhibitor in 2001 paved the way for nearly 100 small-molecule anti-cancer drugs approved by the US FDA and the national medical products administration (NMPA). However, the low response rate and development of drug resistance have posed a major hurdle to improving the progression-free survival (PFS) and overall survival (OS) of cancer patients. Accumulating evidence has enabled scientists and clinicians to strategize the therapeutic approaches of targeting cancer cells and to navigate the development of drug resistance through the continuous monitoring of tumor evolution and oncogenic adaptations. In this review, we highlight the emerging aspects of Hippo signaling in cross-talk with other oncogenic drivers and how this information can be translated into combination therapy to target a broad range of aggressive tumors and the development of drug resistance.

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Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors

Cited by 11 publications

References 31 publications

Chloroacetamide fragment library screening identifies new scaffolds for covalent inhibition of the TEAD·YAP1 interaction

Chloroacetamide fragment library screening identifies new scaffolds for covalent inhibition of the TEAD·YAP1 interaction

ZNL0325, a Pyrazolopyrimidine-Based Covalent Probe, Demonstrates an Alternative Binding Mode for Kinases

Hippo Signaling at the Hallmarks of Cancer and Drug Resistance

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