A Covalent PFKL Activator Suppresses Tumor Growth

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Glycolysis is crucial for cellular functions, and its dysregulation is linked to diseases like cancer, neurodegeneration, and diabetes.
• Cancer cells exhibit the Warburg effect, a metabolic vulnerability that is difficult to exploit due to heterogeneity and resistance.

Purpose of the Study:

• To develop a first-in-class covalent phosphofructokinase-1 liver type (PFKL) activator.
• To create a novel drug delivery mechanism targeting intracellular proteins for cancer therapy.

Main Methods:

• Developed an electrophile-drug conjugate (EDC) that selectively modifies K677 in PFKL.
• Stabilized the R-state tetramer of PFKL to induce metabolic imbalance.
• Delivered cytotoxic payloads to cancer cells in vitro and in vivo.

Main Results:

• The EDC specifically targeted and modified K677 in PFKL's allosteric effector site.
• PFKL activation led to metabolic destabilization in cancer cells.
• The approach demonstrated efficacy in delivering cytotoxic payloads both in vitro and in vivo.

Conclusions:

• Introduced EDCs as a new class of targeted intracellular protein modifiers, analogous to antibody-drug conjugates.
• Demonstrated the potential of covalent PFKL activation for cancer treatment by inducing metabolic imbalance and payload delivery.
• Highlighted EDCs as a versatile platform for selective covalent targeting of intracellular proteins.