Indolequinone-Based Hypoxia-Activated Proteolysis Targeting Chimeras Selectively Degrade BRD4 in Hypoxic Cancer Cells

Area of Science:

• Drug Discovery
• Chemical Biology
• Oncology

Background:

• Proteolysis targeting chimeras (PROTACs) utilize proximity induction for targeted protein degradation.
• Current PROTAC applications face challenges with dose-limiting toxicities due to non-specific protein degradation.
• Context-dependent activation is crucial for safer and more effective PROTAC therapies.

Purpose of the Study:

• To develop hypoxia-activated PROTACs (HAP-TACs) for selective protein degradation in solid tumors.
• To engineer PROTACs that are inactive under normoxic conditions and activated by hypoxia.
• To demonstrate the feasibility of using bioreductive groups for conditional PROTAC activation.

Main Methods:

• An indolequinone bioreductive group was attached to VHL- or cereblon-binding components of PROTACs.
• This modification reduced E3 ligase affinity, rendering the PROTACs inactive.
• Proof-of-concept studies utilized BRD4 degradation as a model system under varying oxygen conditions.

Main Results:

• The indolequinone group was selectively bioreduced under hypoxic conditions.
• This reduction released the active PROTAC, leading to targeted protein degradation.
• BRD4 degradation was observed specifically in hypoxic environments, demonstrating HAP-TAC efficacy.

Conclusions:

• Hypoxia-activated PROTACs (HAP-TACs) offer a novel strategy for targeted protein degradation in hypoxic solid tumors.
• This approach enables context-dependent PROTAC activation, potentially mitigating dose-limiting toxicities.
• The HAP-TAC platform is adaptable to various PROTACs employing VHL or cereblon E3 ligases.