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A covalent PFKL activator suppresses tumor growth
Xiaoding Jiang1, Eric M Lynch2, Congcong Lyu3
1Department of Chemistry, The University of Texas at Austin, Austin, TX, USA.
Abstract:
Glycolysis fuels vital cellular functions, and its dysregulation has been implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, represents a key vulnerability for development of targeted anticancer agents; however, the development of such agents remains challenging owing to metabolic heterogeneity and resistance. Here we developed a covalent phosphofructokinase-1 liver type (PFKL) activator that couples glycolytic activation with delivery of a cytotoxic carnitine palmitoyltransferase 2 (CPT2)-targeting payload to cancer cells in vitro and in vivo. The electrophile-drug conjugate site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL, while concomitantly releasing a CPT2-selective inhibitor to destabilize cell metabolism. The delivery mechanism of electrophile-drug conjugates is analogous to that of antibody-drug conjugates, but differentiated by their selective covalent targeting of intracellular proteins.
Insights
Researchers developed a novel covalent activator for phosphofructokinase-1 liver type (PFKL) that targets cancer cells. This approach simultaneously enhances glycolysis and delivers a cytotoxic payload, offering a new strategy against cancer metabolism.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Glycolysis is crucial for cellular functions, but its dysregulation is linked to diseases like cancer, neurodegeneration, and diabetes.
- Cancer cells exhibit a high reliance on glycolysis, known as the Warburg effect, presenting a therapeutic vulnerability.
- Developing targeted anticancer agents is challenging due to metabolic heterogeneity and resistance mechanisms.
Purpose of the Study:
- To develop a novel covalent activator of phosphofructokinase-1 liver type (PFKL).
- To create a drug conjugate that couples glycolytic activation with targeted delivery of a cytotoxic payload to cancer cells.
- To investigate the efficacy of this approach in vitro and in vivo.
Main Methods:
- Designed and synthesized a covalent phosphofructokinase-1 liver type (PFKL) activator.
- Utilized an electrophile-drug conjugate strategy for site-specific protein modification and payload delivery.
- Tested the conjugate's ability to stabilize PFKL's R-state tetramer and release a carnitine palmitoyltransferase 2 (CPT2)-selective inhibitor.
- Evaluated the conjugate's effects on cancer cell metabolism and viability in vitro and in vivo.
Main Results:
- The developed conjugate selectively modifies K677 in the allosteric effector site of PFKL, stabilizing its R-state tetramer.
- The conjugate effectively delivers a cytotoxic carnitine palmitoyltransferase 2 (CPT2)-targeting payload to cancer cells.
- This dual action leads to enhanced glycolysis activation coupled with metabolic destabilization.
- Demonstrated efficacy of the approach in both in vitro and in vivo cancer models.
Conclusions:
- The novel covalent PFKL activator represents a promising strategy for targeting cancer cell metabolism.
- The electrophile-drug conjugate approach offers a differentiated mechanism for intracellular protein targeting and drug delivery.
- This study highlights a new avenue for developing targeted anticancer agents by exploiting cancer's glycolytic dependency.
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