Discovery of Novel LRPPRC Inhibitors Featuring a Biphenyl-Acylhydrazone Scaffold with Potent Broad-Spectrum Antitumor Activity

  • J Med Chem. 2026 Jul 23;69(14):17118-17141. doi: 10.1021/acs.jmedchem.6c00936.
Hairu Ren  1  2  3 ,  Jie Liu  4  3 ,  Dachi Wang  4  3 ,  Junhao Zhang  1  2  3 ,  Jiayan Zhao  1  2  3 ,  Xin Lai  4  3 ,  Jian Lu  1  2  3 ,  Wei Zhou  4  3 ,  Xuewu Liang  1  3 ,  Xiaohong Fang  4  3 ,  Hong Liu  1  2  3
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 3. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4. Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310018, China.
PMID: 42441917 DOI: 10.1021/acs.jmedchem.6c00936
Abstract

Leucine-rich pentatricopeptide repeat containing (LRPPRC), a critical regulator of mitochondrial gene expression, is overexpressed in various malignancies and sustains Oxidative Phosphorylation (OXPHOS)-dependent adenosine triphosphate (ATP) production essential for tumor growth, chemoresistance, and stem cell survival, rendering it a promising therapeutic target. Herein, using an aptamer-assisted fluorescence polarization platform, we identified acylhydrazone-skeleton inhibitors targeting LRPPRC's RNA-binding domain, leading to the design and synthesis of over 60 derivatives. Lead compound 3o exhibited excellent LRPPRC inhibitory activity (92% at 6.25 μM vs 38% for gossypol acetate (GAA)) and induced robust LRPPRC degradation. Notably, 3o downregulated downstream OXPHOS subunits and ATP Synthase, eliciting broad antiproliferative effects, particularly in refractory and drug-resistant A549, BXPC-3, and NCI-H1975 cells (IC50 = 0.54, 0.27, and 1.39 μM, respectively). In PC9 and HCT116 xenografts, 3o achieved tumor growth inhibition (TGI) rates of 73 and 49% with favorable safety profiles. Overall, we developed novel biphenyl-acylhydrazone LRPPRC inhibitors as potent antitumor agents acting via OXPHOS modulation, providing a valuable lead compound for Cancer therapy.

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