HsClpP-Engaging Selective Mitochondrial Pan-PDK Degraders for Cancer Therapy.

Area of Science:

• Mitochondrial biology
• Cancer therapeutics
• Proteostasis

Background:

• Selective degradation of mitochondrial proteins is challenging due to organelle compartmentalization.
• Pyruvate dehydrogenase kinases (PDKs) regulate mitochondrial metabolism and are implicated in cancer progression.

Purpose of the Study:

• To develop a mitochondria-targeted small molecule degrader for PDKs.
• To investigate the therapeutic potential of PDK degradation in cancer treatment.

Main Methods:

• Design and synthesis of A1, a mitochondria-targeted small molecule.
• Assessment of A1's potency in degrading PDKs and its mechanism of action.
• Evaluation of A1's effects on mitochondrial metabolism, apoptosis, and immunogenic cell death (ICD).
• In vivo studies to assess tumor suppression and systemic toxicity.

Main Results:

• A1 selectively degraded PDKs with nanomolar potency (DC50 ≈ 10 nM) by recruiting HsClpP.
• A1 treatment rewired mitochondrial metabolism, increased oxidative phosphorylation, and induced ROS accumulation.
• A1 triggered mitochondrial apoptosis via mPTP opening and elicited ICD features (CRT exposure, HMGB1 release).
• A1 suppressed primary and distal tumor growth in vivo with selective PDK degradation and no observable systemic toxicity.

Conclusions:

• Mitochondria-targeted degradation of metabolic enzymes, like PDKs, is a viable therapeutic strategy for cancer.
• A1 demonstrates potent anti-tumor efficacy through metabolic reprogramming and induction of immunogenic cell death.
• Targeting mitochondrial proteostasis offers a promising new avenue for cancer therapy.