Development of hypoxia-activated PROTAC exerting a more potent effect in tumor hypoxia than in normoxia

Abstract

In this manuscript, for the first time, we report the development of a kind of hypoxia-activated PROTAC that shows a more potent degradation activity in the tumor hypoxia environment than in normoxia.

Chemistries of bifunctional PROTAC degraders

“…34). 273 They found that compound 212 did not induce the degradation of EGFR protein in normal cells, but the degradation activity of EGFR Del19 was significantly enhanced under hypoxic conditions and it also showed good anti-tumor activity. This is the first example of using hypoxia to activate PROTAC to selectively act on cancer cells, which is providing a new way for the conditionally controlled PROTACs.…”

PROTACs: past, present and future

“…This insufficient oxygen supply results in a hypoxic environment. Recently Cheng et al reported the first Hypoxia-activated PROTAC 121 by using a hypoxia-activated leaving groups (HALGs) to block the EGFR Del19 -based PROTAC (Fig. 17).…”

Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

“…reported the identification of a hypoxia-activated PROTAC (PROTAC 45, Table 12 ) by introducing a hypoxia-activated leaving group (1-methyl-2-nitro-1 H -imidazol-5-yl)methyl or 4-nitrobenzyl into the structure of EGFR Del19 -based PROTAC. 93 PROTAC 45 exhibited stronger degradation activity against EGFR Del19 in HCC4006 cells under hypoxia than in normoxia. This was the first example of using tumour hypoxia to identify PROTACs that acted selectively on tumours, providing a new approach for PROTACs development.…”