2. Academic Validation
  3. Proteome-wide Ligand and Target Discovery by Using Strain-Enabled Cyclopropane Electrophiles

Proteome-wide Ligand and Target Discovery by Using Strain-Enabled Cyclopropane Electrophiles

  • J Am Chem Soc. 2024 Jul 31;146(30):20823-20836. doi: 10.1021/jacs.4c04695.
Yue Liu 1 2 3,  Zhongtang Yu 1 2 3,  Peishan Li 1 2 3,  Tao Yang 1 2 3,  Ke Ding 1 2 3,  Zhi-Min Zhang 1 2 3,  Yi Tan 1 2 3,  Zhengqiu Li 1 2 4 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE), Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 3 School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 4 MOE Key Laboratory of Tumor Molecular Biology, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
PMID: 39018468 DOI: 10.1021/jacs.4c04695
Abstract

The evolving use of covalent ligands as chemical probes and therapeutic agents could greatly benefit from an expanded array of cysteine-reactive electrophiles for efficient and versatile proteome profiling. Herein, to expand the current repertoire of cysteine-reactive electrophiles, we developed a new class of strain-enabled electrophiles based on cyclopropanes. Proteome profiling has unveiled that C163 of Lactate Dehydrogenase A (LDHA) and C88 of adhesion regulating molecule 1 (ADRM1) are ligandable residues to modulate the protein functions. Moreover, fragment-based ligand discovery (FBLD) has revealed that one fragment (Y-35) shows strong reactivity toward C66 of thioredoxin domain-containing protein 12 (TXD12), and its covalent binding has been demonstrated to impact its downstream signal pathways. TXD12 plays a pivotal role in enabling Y-35 to exhibit its antisurvival and antiproliferative effects. Finally, dicarbonitrile-cyclopropane has been demonstrated to be an electrophilic warhead in the development of GSTO1-involved dual covalent inhibitors, which is promising to alleviate drug resistance.

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