PROTAC Synthesis
PROTAC molecules are generally composed of three parts: ligand for target protein, linker and ligand for E3 ligase. “Click chemistry” reactions provide an accessible and tunable strategy for the selection of synthetic linkers and lay a solid foundation for the development of a diverse library of PROTACs in biomedical research. The copper-catalyzed reaction is typically high yielding, requiring stoichiometric quantities of each component and boasts excellent functional group compatibility under mild reaction conditions. This approach would allow for the parallel synthesis of libraries of PROTACs provided the necessary azides and alkynes could be prepared. For example, click chemistry was utilized to prepare a library of PROTACs based on entinostat a class I histone deacetylase (HDAC) inhibitor in clinical trials. Recently, an advanced PROTAC technology was developed, namely CLIPTAC (in-cell click-formed proteolysis-targeting chimeras), with two precursor components combined by bioorthogonal “click” reaction.
- Formula: C69H94N12O16
- Molecular Weight: 1347.56
DBCO-(PEG2-Val-Cit-PAB)2 is a dual cleavable ADC linker for antibody-drug conjugates (ADCs). DBCO-(PEG2-Val-Cit-PAB)2 is also a PEG-based PROTAC linker that can be used in the synthesis of PROTACs. DBCO-(PEG2-Val-Cit-PAB)2 is a click chemistry reagent, it contains a DBCO group that can undergo strain-promoted alkyne-azide cycloaddition (SPAAC) with molecules containing Azide groups.
- Formula: C14H14N2O3
- Molecular Weight: 258.27
CRBN ligand-911 is an E3 ligase ligand that targets CRBN. CRBN ligand-911 forms a stable ternary complex with CRBN to enable proximity-induced co-binding and ubiquitination of LIMK2. CRBN ligand-911 binds directly to CRBN. CRBN ligand-911 is used for the synthesis of the LIMK2-targeting PROTAC degrader THNAN69 (HY-178122).
- Formula: C20H22N4O4
- Molecular Weight: 382.41
Lenalidomide-CO-C3-NH-alkynes is an E3 ligase ligand-linker conjugate comprising Lenalidomide (HY-A0003) and a linker. Acepromazine-1-piperazinepropanamine dihydrochloride can be conjugated to a target protein ligand to form a PROTAC molecule—for instance, the PROTAC EGFR degrader 7 (HY-147858).
- Formula: C8H14O
- Molecular Weight: 126.20
- Formula: C29H40N6O8
- Molecular Weight: 600.66
Pomalidomid-C6-PEG3-butyl-N3 is an E3 ligase-linker conjugate that can be used for the synthesis of PROTACs.
- Formula: 13C4H9ClN2 15N2O2
- Molecular Weight: 186.55
L-Azidohomoalanine-1,2,3,4-13C4 (hydrochloride) is the 13C- and 15N-labeled L-Azidohomoalanine hydrochloride. L-Azidohomoalanine hydrochloride is an alkyl chain-based PROTAC linker that can be used in the synthesis of PROTACs. L-Azidohomoalanine-1,2,3,4-13C4 (hydrochloride) is a click chemistry reagent, it contains an Azide group and can undergo copper-catalyzed azide-alkyne cycloaddition reaction (CuAAc) with molecules containing Alkyne groups. It can also undergo strain-promoted alkyne-azide cycloaddition (SPAAC) reactions with molecules containing DBCO or BCN groups.
- Formula: C31H55N3O14S
- Molecular Weight: 725.85
Azide-PEG12-Tos is a PEG-based PROTAC linker that can be used in the synthesis of PROTACs. Azide-PEG12-Tos is a click chemistry reagent, it contains an Azide group and can undergo copper-catalyzed azide-alkyne cycloaddition reaction (CuAAc) with molecules containing Alkyne groups. It can also undergo strain-promoted alkyne-azide cycloaddition (SPAAC) reactions with molecules containing DBCO or BCN groups.
- Formula: C9H16N4O3S
- Molecular Weight: 260.31
1-Isothiocyanato-PEG3-azide is a PEG-based PROTAC linker that can be used in the synthesis of PROTACs. 1-Isothiocyanato-PEG3-azide is a click chemistry reagent, it contains an Azide group and can undergo copper-catalyzed azide-alkyne cycloaddition reaction (CuAAc) with molecules containing Alkyne groups. It can also undergo strain-promoted alkyne-azide cycloaddition (SPAAC) reactions with molecules containing DBCO or BCN groups.
- Formula: C24H34N2O9
- Molecular Weight: 494.53
- Formula: C22H45N3O11
- Molecular Weight: 527.61
Azido-PEG11-alcohol is a PEG-based PROTAC linker that can be used in the synthesis of PROTACs. Azido-PEG11-alcohol is a click chemistry reagent, it contains an Azide group and can undergo copper-catalyzed azide-alkyne cycloaddition reaction (CuAAc) with molecules containing Alkyne groups. It can also undergo strain-promoted alkyne-azide cycloaddition (SPAAC) reactions with molecules containing DBCO or BCN groups.
