2. Academic Validation
  3. Discovery of novel 2-azabicyclo[3.2.1]octane derivatives against non-small cell lung cancer from aconitine simplification

Discovery of novel 2-azabicyclo[3.2.1]octane derivatives against non-small cell lung cancer from aconitine simplification

  • Bioorg Chem. 2026 Jan:168:109360. doi: 10.1016/j.bioorg.2025.109360.
Shuai Guo 1,  Ting-Ting Li 1,  Gong-Hui Ge 1,  Hao Hu 1,  Wen-Han Xue 1,  Yan-Ping Wang 1,  Xu Zhang 1,  Hong-Ye Liu 1,  Jing-Wei Liang 2,  Yi Zhang 3,  Fan-Hao Meng 4,  Ting-Jian Zhang 5
Affiliations

Affiliations

  • 1 School of Pharmacy / Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China.
  • 2 Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Provincial Key Laboratory of Research and Development on Tropical Herbs, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou 571199, Hainan, China; School of Pharmacy, Hainan Medical University, Haikou 571199, Hainan, China.
  • 3 School of Pharmacy / Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China; School of Pharmacy, Anhui Xinhua University, 555 Wangjiangxi Road, High-tech Zone, Hefei 230088, China. Electronic address: [email protected].
  • 4 School of Pharmacy / Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China. Electronic address: [email protected].
  • 5 School of Pharmacy / Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China; Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Provincial Key Laboratory of Research and Development on Tropical Herbs, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou 571199, Hainan, China. Electronic address: [email protected].
PMID: 41386066 DOI: 10.1016/j.bioorg.2025.109360
Abstract

Aconitine, a diterpenoid alkaloid, exhibits promising bioactivities, but its clinical application is limited by severe toxicity. Through a structural simplification and derivatization strategy, we designed and synthesized a novel series of 2-azabicyclo[3.2.1]octane derivatives. This effort culminated in the identification of compound 8q, which demonstrated potent and selective anti-tumor efficacy against ALK (anaplastic lymphoma kinase) -positive Cancer cells (NCI-H2228 and Karpas-299), significantly outperforming ceritinib in enzymatic and cellular assays. Mechanism studies revealed that 8q effectively inhibits ALK phosphorylation and its downstream PI3K/Akt/mTOR and Ras/MEK/ERK signaling pathways, inducing G0/G1 phase cell cycle arrest and Apoptosis. Moreover, 8q markedly suppressed Cancer cell migration and invasion. In an NCI-H2228 xenograft model, 8q exhibited dose-dependent tumor growth inhibition, with the high-dose group (60 mg/kg) showing superior efficacy to ceritinib (30 mg/kg) and no significant systemic or organ toxicity. Molecular docking and dynamics simulations revealed that 8q stably binds within the ATP-binding pocket of ALK, forming key interactions with residues in the hinge (Glu1197) and solvent-front (Glu1269 and Asp1270) regions. The RMSD and RMSF analyses confirmed enhanced conformational stability of the 8q-ALK complex compared to the apo protein. Collectively, these findings highlight 8q as a promising lead compound for the development of novel ALK inhibitors with a favorable efficacy and safety profile.

Keywords

Aconitine; Anaplastic lymphoma kinase; Antiproliferative activity; Non-small cell lung cancer; Structural simplification.

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