2. Academic Validation
  3. Comprehensive Chemoproteomics Unveils Selective HMG-CoA Synthase 1 Inhibitors for Targeting Mevalonate Metabolism in Cancer

Comprehensive Chemoproteomics Unveils Selective HMG-CoA Synthase 1 Inhibitors for Targeting Mevalonate Metabolism in Cancer

  • J Am Chem Soc. 2026 May 27;148(20):20705-20719. doi: 10.1021/jacs.6c02556.
Liang Sun 1,  Sang Ah Yi 1 2 3,  Brittany Q Pham 1 4,  Antoine Mocellin 5,  Sagnik Sen 6,  M Jason de la Cruz 6 7,  Alban Ordureau 5,  Heeseon An 1 4 8
Affiliations

Affiliations

  • 1 Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
  • 2 School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
  • 3 Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea.
  • 4 Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, United States.
  • 5 Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
  • 6 Structural Biology Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
  • 7 Structural Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
  • 8 Tri-Institutional PhD Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
PMID: 42127206 DOI: 10.1021/jacs.6c02556
Abstract

Comprehensive target validation remains a significant bottleneck in chemical probe development, particularly for covalent inhibitors, where off-target reactivity can lead to toxicity. Using HMG-CoA synthase 1 (HMGCS1), an underexplored gatekeeper enzyme in the mevalonate pathway, we demonstrate how integrating orthogonal chemoproteomic methods can provide unbiased, comprehensive insights into the on- and off-target profiles of covalent inhibitors. Our study specifically highlights the limitations of traditional enrichment proteomics in distinguishing high-occupancy Binders from low-occupancy Binders, and it proposes a solution through a complementary scavenging proteomics approach that analyzes de-enriched fractions, providing target engagement ratios across the proteome. This framework facilitated the development of CNP7, a cyanopyrrolidine that covalently modifies HMGCS1's catalytic cysteine with remarkable selectivity, as assessed by comprehensive chemoproteomics. A 2.29 Å cryo-EM structure reveals how CNP7 engages the catalytic cysteine within HMGCS1's hydrophobic pocket. CNP7 treatment decreases HMG-CoA levels and induces global protein deprenylation within 4 h. Notably, CNP7 exhibits cell line-specific Anticancer activity patterns that differ from those of statins, suggesting possible pathway node-specific vulnerabilities. Together, our study offers valuable chemical tools to modulate HMGCS1 activity and presents a framework for the rigorous characterization of covalent inhibitors in chemical biology and drug development.

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