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Merck

Light-induced control of protein destruction by opto-PROTAC.

Science advances (2020-03-05)
Jing Liu, He Chen, Leina Ma, Zhixiang He, Dong Wang, Yi Liu, Qian Lin, Tinghu Zhang, Nathanael Gray, H Ümit Kaniskan, Jian Jin, Wenyi Wei
ABSTRACT

By hijacking endogenous E3 ligase to degrade protein targets via the ubiquitin-proteasome system, PROTACs (PRoteolysis TArgeting Chimeras) provide a new strategy to inhibit protein targets that were regarded as undruggable before. However, the catalytic nature of PROTAC potentially leads to uncontrolled degradation that causes systemic toxicity issues, limiting the application of PROTAC in the clinic. Here, we introduce a light-inducible switch on PROTACs, thereafter termed as opto-PROTAC, to enable the degradation of protein targets in a spatiotemporal manner. By adding a photolabile caging group on pomalidomide as a parental compound and two additional PROTACs, dBET1 and dALK, we demonstrated light-inducible protein degradation. These opto-PROTACs display no activities in the dark, while the restricted degradation can be induced at a specific time and rate by ultraviolet A irradiation. Our approach provides a generalizable platform for the development of light-controlled PROTACs and enables PROTAC to be a precision medicine.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Pomalidomide, ≥98% (HPLC)
Sigma-Aldrich
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
Millipore
Monoclonal Anti-HA−Agarose antibody produced in mouse, clone HA-7, purified immunoglobulin, PBS suspension
Millipore
ANTI-FLAG® M2 Affinity Gel, purified immunoglobulin, buffered aqueous glycerol solution
Sigma-Aldrich
Opto-pomalidomide-C2-NH2 hydrochloride, ≥95%
Sigma-Aldrich
Opto-pomalidomide, ≥95%
Sigma-Aldrich
Opto-thalidomide-O-acetamide-C4-NH2 hydrochloride