Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead <b>MSC-4106</b>

Heinrich, Timo; Peterson, Carl R.; Schneider, Richard; Garg, Sakshi; Schwarz, Dániel; Gunera, Jakub; Seshire, Anita; Kötzner, Lisa; Schlesiger, Sarah; Müsil, Djordje; Schilke, Heike; Doerfel, Benjamin; Diehl, Patrizia; Böpple, Pia; Lemos, Ana R.; Sousa, Pedro M. F.; Freire, Filipe; Bandeiras, Tiago M.; Carswell, Emma L.; Pearson, Nicholas; Sirohi, Sameer; Hooker, Mollie; Trivier, Elisabeth; Broome, Rebecca; Balsiger, Alexander; Crowden, Abigail; Dillon, Christian; Wienke, Dirk

doi:10.1021/acs.jmedchem.2c00403

Cited by 25 publications

(16 citation statements)

References 30 publications

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“…The proportion of entries in this category (entries 12–17) targeted by F2L campaigns has remained roughly constant this year at 34% compared with 29% in the previous year (and 25% of the total entries over the years), with only one of these being a bromodomain (entry 12). – Entry 13 describes the discovery of clinical candidate BI 1823911, a covalent inhibitor of the G12C mutant of KRAS. Unusually for this target, the researchers performed a noncovalent fragment screen and used structure-based drug design (SBDD) to optimize the reversible inhibitor before addition of the covalent warhead at the end.…”

Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Woodhead,

Erlanson,

de Esch

et al. 2024

J. Med. Chem.

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This Perspective is the eighth in an annual series that summarizes successful fragment-to-lead (F2L) case studies published each year. A tabulated summary of relevant articles published in 2022 is provided, and features such as target class, screening methods, and ligand efficiency are discussed both for the 2022 examples and for the combined examples over the years 2015−2022. In addition, trends and new developments in the field are summarized. In 2022, 18 publications described successful fragment-to-lead studies, including the development of three clinical compounds (MTRX1719, MK-8189, and BI-823911). ■ SIGNIFICANCEFragment-based methodologies have become firmly established within the drug discovery community, and with the recent FDA approval of capivasertib, there are now seven fragment-derived drugs approved for clinical use. This Perspective provides case studies of successful fragment-tolead examples for 2022 and discusses various trends, including target classes, screening methods, and physicochemical properties, compared with previous years.

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Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Woodhead,

Erlanson,

de Esch

et al. 2024

J. Med. Chem.

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“…This could be due to less efficient inhibition of palmitoylation or higher expression of TEAD3. The volume of the palmitic acid binding pocket in TEAD3 is significantly different than the other isoforms due to Y230, V331 and F414 ( 43 ). Further, Y230 and F414 are predicted to profoundly influence the shape of this site.…”

Section: Discussionmentioning

confidence: 98%

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

2022

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The paralogous oncogenic transcriptional coactivators YAP and TAZ are the distal effectors of the Hippo signaling pathway, which plays a critical role in cell proliferation, survival and cell fate specification. They are frequently deregulated in most human cancers, where they contribute to multiple aspects of tumorigenesis including growth, metabolism, metastasis and chemo/immunotherapy resistance. Thus, they provide a critical point for therapeutic intervention. However, due to their intrinsically disordered structure, they are challenging to target directly. Since YAP/TAZ exerts oncogenic activity by associating with the TEAD1-4 transcription factors, to regulate target gene expression, YAP activity can be controlled indirectly by regulating TEAD1-4. Interestingly, TEADs undergo autopalmitoylation, which is essential for their stability and function, and small-molecule inhibitors that prevent this posttranslational modification can render them unstable. In this article we report discovery of a novel small molecule inhibitor of YAP activity. We combined structure-based virtual ligand screening with biochemical and cell biological studies and identified JM7, which inhibits YAP transcriptional reporter activity with an IC50 of 972 nMoles/Ltr. Further, it inhibits YAP target gene expression, without affecting YAP/TEAD localization. Mechanistically, JM7 inhibits TEAD palmitoylation and renders them unstable. Cellular thermal shift assay revealed that JM7 directly binds to TEAD1-4 in cells. 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.

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“…Therefore, there is growing enthusiasm in both industry and academia to develop TEAD palmitate-binding pocket (PBP) inhibitors as an alternate way to modulate TEAD-YAP signaling. A deluge of TEAD investigational inhibitors has been disclosed including VT-107, MGH-CP-1, TM2, compound 2 , and MSC-4106 and cysteine-directing covalent inhibitors such as TED-347, DC-TEADin02, DC-TEAD3in03, kojic acid analogues, MYF-01-037, and K-975 (Figure ). Moreover, three TEAD inhibitors IK930, VT3989, and IAG933 have progressed into clinical trials (NCT05228015, NCT04665206, and NCT04857372) as monotherapy in subjects with advanced solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors

Fan

et al. 2023

J. Med. Chem.

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Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yesassociated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are important transcription factors and cofactors that regulate gene expression in the Hippo pathway. In mammals, the TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant expression and hyperactivation of TEAD/YAP signaling have been implicated in a variety of malignancies. Recently, TEADs were recognized as being palmitoylated in cells, and the lipophilic palmitate pocket has been successfully targeted by both covalent and noncovalent ligands. In this report, we present the medicinal chemistry effort to develop MYF-03-176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03-176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.

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Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106

Cited by 25 publications

References 30 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Fragment-to-Lead Medicinal Chemistry Publications in 2022

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

Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors

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