2. Academic Validation
  3. HSP90/LSD1 dual inhibitors against prostate cancer as well as patient-derived colorectal organoids

HSP90/LSD1 dual inhibitors against prostate cancer as well as patient-derived colorectal organoids

  • Eur J Med Chem. 2024 Nov 15:278:116801. doi: 10.1016/j.ejmech.2024.116801.
Di-Wei Tang 1,  I-Chung Chen 1,  Po-Yu Chou 1,  Mei-Jung Lai 2,  Zheng-Yang Liu 1,  Kelvin K Tsai 3,  Li-Hsin Cheng 4,  Jian-Xun Zhao 1,  Er-Chieh Cho 5,  Hung-Hsuan Chang 1,  Tony Eight Lin 6,  Kai-Cheng Hsu 6,  Mei-Chuan Chen 7,  Jing-Ping Liou 8
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 2 TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan.
  • 3 Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Organoids Technology Core, Taipei Medical University, Taipei, Taiwan.
  • 4 Organoids Technology Core, Taipei Medical University, Taipei, Taiwan.
  • 5 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Master Program in Clinical Genomics and Proteomics, Taipei Medical University, Taipei, Taiwan.
  • 6 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 7 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Traditional Herbal Medicine Research, Center of Taipei Medical University Hospital, Taipei, Taiwan; Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: mcchen1250@tmu.edu.tw.
  • 8 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: jpl@tmu.edu.tw.
PMID: 39241481 DOI: 10.1016/j.ejmech.2024.116801
Abstract

The rational installation of pharmacophores targeting HSP90 and LSD1 axes has achieved significant anti-cancer capacity in prostate and colorectal Cancer. Among the series of hybrids, inhibitor 6 exhibited remarkable anti-proliferative activity against prostate Cancer cell lines PC-3 and DU145, with GI50 values of 0.24 and 0.30 μM, respectively. It demonstrated notable efficacy in combinatorial attack and cell death initiation towards Apoptosis. The cell death process was mediated by PARP induction and γH2AX signaling, and was also characterized as caspase-dependent and Bcl-xL/Bax-independent. Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound 6 compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 μM, compound 6 effectively inhibited the growth of patient-derived colorectal Cancer (CRC) organoids for up to 10 days in vitro. Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy.

Keywords

CRC organoids; Dual inhibitor; HSP90; LSD1; Prostate cancer; Resistance.

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