2. Academic Validation
  3. Discovery of novel, potent, and orally bioavailable HDACs inhibitors with LSD1 inhibitory activity for the treatment of solid tumors

Discovery of novel, potent, and orally bioavailable HDACs inhibitors with LSD1 inhibitory activity for the treatment of solid tumors

  • Eur J Med Chem. 2023 Jun 5;254:115367. doi: 10.1016/j.ejmech.2023.115367.
Yingchao Duan 1,  Tong Yu 2,  Linfeng Jin 2,  Shaojie Zhang 2,  Xiaojing Shi 3,  Yizhe Zhang 2,  Nanqian Zhou 4,  Yongtao Xu 5,  Wenfeng Lu 6,  Huimin Zhou 2,  Huijuan Zhu 2,  Suping Bai 2,  Kua Hu 7,  Yuanyuan Guan 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Xinxiang Medical University, 453003, Xinxiang, Henan Province, PR China. Electronic address: [email protected].
  • 2 School of Pharmacy, Xinxiang Medical University, 453003, Xinxiang, Henan Province, PR China.
  • 3 Laboratory Animal Center, Academy of Medical Science, Zhengzhou University, 450052, Zhengzhou, Henan Province, PR China.
  • 4 Department of Ultrasonography, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan University People's Hospital, 450003, Zhengzhou, Henan Province, PR China.
  • 5 School of Medical Engineering, Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang Medical University, 453003, Xinxiang, Henan Province, PR China. Electronic address: [email protected].
  • 6 School of Medical Engineering, Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang Medical University, 453003, Xinxiang, Henan Province, PR China.
  • 7 School of Pharmacy, Xinxiang Medical University, 453003, Xinxiang, Henan Province, PR China. Electronic address: [email protected].
  • 8 School of Pharmacy, Xinxiang Medical University, 453003, Xinxiang, Henan Province, PR China. Electronic address: [email protected].
PMID: 37086699 DOI: 10.1016/j.ejmech.2023.115367
Abstract

Histone deacetylases (HDACs) and lysine-specific demethylase 1 (LSD1) are attractive targets for epigenetic Cancer therapy. There is an intimate interplay between the two enzymes. HDACs inhibitors have shown synergistic Anticancer effects in combination with LSD1 inhibitors in several types of Cancer. Herein, we describe the discovery of compound 5e, a highly potent HDACs inhibitor (HDAC1/2/6/8; IC50 = 2.07/4.71/2.40/107 nM) with anti-LSD1 potency (IC50 = 1.34 μM). Compound 5e exhibited marked antiproliferative activity in several Cancer cell lines. 5e effectively induced mitochondrial Apoptosis with G2/M phase arrest, inhibiting cell migration and invasion in MGC-803 and HCT-116 Cancer cells. It also showed good liver microsomal stability and acceptable pharmacokinetic parameters in SD rats. More importantly, orally administered compound 5e demonstrated higher in vivo antitumor efficacy than SAHA in the MGC-803 (TGI = 71.5%) and HCT-116 (TGI = 57.6%) xenograft tumor models accompanied by good tolerability. This study provides a novel lead compound with dual inhibitory activity against HDACs and LSD1 to further develop epigenetic drugs for solid tumor therapy. Further optimization is needed to improve the LSD1 activity to achieve dual inhibitors with balanced potency on LSD1 and HDACs.

Keywords

Dual inhibitors; HDACs; LSD1; Solid tumors.

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