2. Academic Validation
  3. Discovery of Novel 4,5-Dihydropyrrolo[3,4- c]pyrazol-6(2H)-one-Based Tubulin Inhibitors Targeting Colchicine Binding Site with Potent Anti-Ovarian Cancer Activity

Discovery of Novel 4,5-Dihydropyrrolo[3,4- c]pyrazol-6(2H)-one-Based Tubulin Inhibitors Targeting Colchicine Binding Site with Potent Anti-Ovarian Cancer Activity

  • J Med Chem. 2025 Oct 9;68(19):19908-19932. doi: 10.1021/acs.jmedchem.5c00014.
Quanwei Yu 1 2 3 4 5,  Yujie Liu 1 2 3 4,  Zhijia Wang 1 2 3 4,  Chengyong Wu 1 2 3 4,  Ruofei Zhang 1 2 3 4,  Lun Tan 1,  Lele Zhang 1,  Cuiyu Guo 1 2 3 4,  Lantu Gou 1 2 3 4,  Weimin Li 1 2 3 4,  Yang He 1 2 3 4,  Yuxi Wang 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 State Key Laboratory of Respiratory Health and Multimorbidity, Sichuan University, Chengdu 610041, China.
  • 5 Heilongjiang Institute for Drug Control, Harbin 150088, China.
PMID: 40974592 DOI: 10.1021/acs.jmedchem.5c00014
Abstract

To address the toxicity of current microtubule inhibitors, we employed the GeminiMol deep learning model to screen the Zinc20 database, identifying a novel 4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one scaffold (Y1) targeting the colchicine binding site. Subsequent optimization culminated in Y60s, a potent antiproliferative agent (SKOV3 IC50 = 0.025 μM) that inhibits clonogenic formation, migration, and invasion of ovarian Cancer cells. Y60s inhibited tubulin polymerization which in turn induced G2/M arrest and Apoptosis in SKOV3 cells. Y60s demonstrated potent antitumor activity without observable toxicity in an SKOV3 xenograft model. The cocrystal structure of Y8 in complex with tubulin was resolved, confirming the key binding mode of 4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one compounds. This work showcases Y60s as a promising novel tubulin inhibitor and highlights the utility of deep learning model for rapid identification of bioactive compounds from large chemical databases.

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