A platform for the rapid synthesis of proteolysis targeting chimeras (Rapid-TAC) under miniaturized conditions

Guo, Le; Yun, Zhou; Nie, Xueqing; Zhang, Zhongrui; Zhang, Zhen; Li, Chunrong; Wang, Taobo; Tang, Weiping

doi:10.1016/j.ejmech.2022.114317

Cited by 26 publications

(20 citation statements)

References 29 publications

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“…Therefore, rapid construction of a large number of PROTAC compound libraries for activity screening is the future direction of PROTAC technology. 122,123 In 2022, Tang et al reported a platform for the rapid synthesis of PROTAC compound libraries based on a traceless OPA-amine coupling reaction for screening AR and BRD4 degraders. 123 Firstly, the POI ligand motif coupled with ortho-phthalaldehyde (OPA) (62) needs to be prepared in advance.…”

Section: Assembly Of Protacsmentioning

confidence: 99%

“…122,123 In 2022, Tang et al reported a platform for the rapid synthesis of PROTAC compound libraries based on a traceless OPA-amine coupling reaction for screening AR and BRD4 degraders. 123 Firstly, the POI ligand motif coupled with ortho-phthalaldehyde (OPA) (62) needs to be prepared in advance. Commercially available E3 ligase ligand-linker-NH 2 building blocks (63) with different E3 ligase ligands and various types and lengths of linkers provide diversity for the PROTAC library.…”

Section: Assembly Of Protacsmentioning

confidence: 99%

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Chemistries of bifunctional PROTAC degraders

Cao

Wang

et al. 2022

Chem. Soc. Rev.

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Section: Assembly Of Protacsmentioning

confidence: 99%

Section: Assembly Of Protacsmentioning

confidence: 99%

Chemistries of bifunctional PROTAC degraders

Cao

Wang

et al. 2022

Chem. Soc. Rev.

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“…Many efforts have been made to improve the synthesis efficiency of PROTACs. Current strategies for increasing synthetic throughput have been introduced through Staudinger ligation chemistry, solid-phase synthesis, copper-catalyzed click chemistry, activated esters, the rapid synthesis of PROTACs (Rapid-TAC) platform, and the modular synthetic platform . Notably, a late-stage single-step reductive deoxygenation method allows immediate conversion from thalidomide-containing PROTACs to lenalidomide groups without a de novo synthesis .…”

Section: Protac Design Strategymentioning

confidence: 99%

Advancing Strategies for Proteolysis-Targeting Chimera Design

Zhi

Liu

et al. 2023

J. Med. Chem.

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Proteolysis-targeting chimeras (PROTACs) have shown great therapeutic potential by degrading various disease-causing proteins, particularly those related to tumors. Therefore, the introduction of PROTACs has ushered in a new chapter of antitumor drug development, marked by significant advances over recent years. Herein, we describe recent developments in PROTAC technology, focusing on design strategy, development workflow, and future outlooks. We also discuss potential opportunities and challenges for PROTAC research.

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“…Direct-to-biology and miniaturised approaches have also been developed to speed up the DMTA cycle. 19,20 However, all these strategies rely on the prefunctionalisation of the POI-ligand with a suitable functional handle along the desired exit vector(s). This itself often represents a considerable synthetic hurdle, and modular and reliable approaches to streamline the synthesis of PROTACs continue to be in high demand.…”

Section: Introductionmentioning

confidence: 99%

Ruthenium-catalysed C‒H amidation for the late-stage synthesis of PROTACs

Antermite

Friis

Johansson

et al. 2023

Preprint

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PROteolysis TArgeting Chimeras (PROTACs) are a powerful modality in drug discovery, offering the potential to address outstanding medical challenges. However, the synthetic feasibility of PROTACs, and the empiric and complex nature of their structure-activity relationships continue to present formidable limitations. As such, modular and reliable approaches to streamline the synthesis of these compounds are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to provide modular access to both fully elaborated PROTACs and drug conjugates. Using readily available dioxazolone reagents, a broad range of inherently present functional groups can guide the C–H amidation on complex bioactive molecules. High selectivity and functional group tolerance enable the late-stage installation of linkers bearing orthogonal functional handles for downstream elaboration. Finally, the single-step synthesis of PROTAC and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools.

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A platform for the rapid synthesis of proteolysis targeting chimeras (Rapid-TAC) under miniaturized conditions

Cited by 26 publications

References 29 publications

Chemistries of bifunctional PROTAC degraders

Chemistries of bifunctional PROTAC degraders

Advancing Strategies for Proteolysis-Targeting Chimera Design

Ruthenium-catalysed C‒H amidation for the late-stage synthesis of PROTACs

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