A Concise Synthetic Approach to Highly Reactive Click‐to‐Release <i>Trans</i>‐Cyclooctene Linkers**

Liu, Bing; ten Hoeve, Wolter; Versteegen, Ron M.; Rossin, Raffaella; Kleijn, Laurens H. J.; Robillard, Marc S.

doi:10.1002/chem.202300755

Cited by 10 publications

(1 citation statement)

References 18 publications

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“…Besides, to address the low DAR of conventional coupling techniques, Dantari's T‐HDC technology “packages” the payload by using polymer molecules and then couples the polymer‐packaged payload to the antibody. This load‐release system can carry more payloads, and one antibody can carry more than 60 payload molecules [ 78 ]. Dolaflexin, a multiwarhead ADC platform of Mersana, also uses polymers to develop high DAR ADC drugs.…”

Section: Future Developments On Adcsmentioning

confidence: 99%

Development of antibody‐drug conjugates in cancer: Overview and prospects

Ruan,

Wu,

Meng

et al. 2023

Cancer Communications

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In recent years, remarkable breakthroughs have been reported on antibody‐drug conjugates (ADCs), with 15 ADCs successfully entering the market over the past decade. This substantial development has positioned ADCs as one of the fastest‐growing domains in the realm of anticancer drugs, demonstrating their efficacy in treating a wide array of malignancies. Nonetheless, there is still an unmet clinical need for wider application, better efficacy, and fewer side effects of ADCs. An ADC generally comprises an antibody, a linker and a payload, and the combination has profound effects on drug structure, pharmacokinetic profile and efficacy. Hence, optimization of the key components provides an opportunity to develop ADCs with higher potency and fewer side effects. In this review, we comprehensively reviewed the current development and the prospects of ADC, provided an analysis of marketed ADCs and the ongoing pipelines globally as well as in China, highlighted several ADC platforms and technologies specific to different pharmaceutical enterprises and biotech companies, and also discussed the new related technologies, possibility of next‐generation ADCs and the directions of clinical research.

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Section: Future Developments On Adcsmentioning

confidence: 99%

Development of antibody‐drug conjugates in cancer: Overview and prospects

Ruan,

Wu,

Meng

et al. 2023

Cancer Communications

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Hydroxylierte Aryl‐Tetrazine als bioorthogonale Scheren zur systematischen Spaltung von trans‐Cyclooctenen

Wilkovitsch,

Kuba,

Keppel

et al. 2024

Angewandte Chemie

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Bioorthogonale Bindungsspaltungsreaktionen haben sich als leistungsstarke Werkzeuge für die präzise zeitliche und räumliche Kontrolle (bio)molekularer Funktionen in biologischen Systemen etabliert. Unter diesen sticht die durch Click‐Reaktion mit Tetrazinen ausgelöste Eliminierung spaltbarer trans‐Cyclooctene (Click‐Spaltung, engl. Click‐to‐Release) aufgrund hoher Reaktionsraten sowie ihrer Vielseitigkeit und Selektivität hervor. Trotz des zunehmenden Verständnisses der zugrunde liegenden Mechanismen ist die Anwendung dieser Reaktion aufgrund unzureichender Eigenschaften (Click‐Kinetik, Spaltungskinetik, Spaltungseffizienz) der bestehenden Reagenzien eingeschränkt. Eine effiziente Spaltung war bisher auf Tetrazine mit vergleichsweise niedriger Click‐Reaktivität beschränkt, während hochreaktive Aryl‐Tetrazine nur eine minimale Spaltung erzielen. Durch die Einführung von Hydroxylgruppen an Phenyl‐ und Pyridyl‐Tetrazinen ist es uns gelungen, eine neue Klasse von ′bioorthogonalen Scheren′ mit hoher chemischer Leistungsfähigkeit zu entwickeln. Diese Hydroxyaryl‐Tetrazine erreichen eine nahezu quantitative Spaltung nach beschleunigter Click‐Reaktion mit unterschiedlichen spaltbaren trans‐Cyclooctenen, was durch die Click‐ausgelöste Aktivierung einer Wirkstoffvorstufe (engl. Prodrug), die intramitochondriale Spaltung einer fluorogenen Sonde in lebenden Zellen und die schnelle intrazelluläre bioorthogonale Spaltung eines Ligand‐Farbstoff‐Konjugats demonstriert wird.

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Sulfonated Hydroxyaryl‐Tetrazines with Increased pK_a for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells

Rahm,

Keppel,

Šlachtová

et al. 2024

Angewandte Chemie

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Bioorthogonal reactions that enable switching molecular functions by breaking chemical bonds have gained prominence, with the tetrazine‐mediated cleavage of trans‐cyclooctene caged compounds (click‐to‐release) being particularly noteworthy for its high versatility, biocompatibility, and fast reaction rates. Despite several recent advances, the development of highly reactive tetrazines enabling quantitative elimination from trans‐cyclooctene linkers remains challenging. In this study, we present the synthesis and application of sulfo‐tetrazines, a class of derivatives featuring phenolic hydroxyl groups with increased acidity constants (pKa). This unique property leads to accelerated elimination and complete release of the caged molecules within minutes. Moreover, the inclusion of sulfonate groups provides a valuable synthetic handle, enabling further derivatization into sulfonamides, modified with diverse substituents. Significantly, we demonstrate the utility of sulfo‐tetrazines in efficiently activating fluorogenic compounds and prodrugs in living cells, offering exciting prospects for their application in bioorthogonal chemistry.

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A Concise Synthetic Approach to Highly Reactive Click‐to‐Release Trans‐Cyclooctene Linkers**

Cited by 10 publications

References 18 publications

Development of antibody‐drug conjugates in cancer: Overview and prospects

Development of antibody‐drug conjugates in cancer: Overview and prospects

Hydroxylierte Aryl‐Tetrazine als bioorthogonale Scheren zur systematischen Spaltung von trans‐Cyclooctenen

Sulfonated Hydroxyaryl‐Tetrazines with Increased pK_a for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells

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A Concise Synthetic Approach to Highly Reactive Click‐to‐Release Trans‐Cyclooctene Linkers**

Cited by 10 publications

References 18 publications

Development of antibody‐drug conjugates in cancer: Overview and prospects

Development of antibody‐drug conjugates in cancer: Overview and prospects

Hydroxylierte Aryl‐Tetrazine als bioorthogonale Scheren zur systematischen Spaltung von trans‐Cyclooctenen

Sulfonated Hydroxyaryl‐Tetrazines with Increased pKa for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells

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Product

Resources

About

Sulfonated Hydroxyaryl‐Tetrazines with Increased pK_a for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells