发现具有LSD1抑制活性的新型、有效的口服可生物利用性HDAC抑制剂，用于实体肿瘤的治疗。
Discovery of novel, potent, and orally bioavailable HDACs inhibitors with LSD1 inhibitory activity for the treatment of solid tumors.
发表日期：2023 Apr 14
作者：
Yingchao Duan, Tong Yu, Linfeng Jin, Shaojie Zhang, Xiaojing Shi, Yizhe Zhang, Nanqian Zhou, Yongtao Xu, Wenfeng Lu, Huimin Zhou, Huijuan Zhu, Suping Bai, Kua Hu, Yuanyuan Guan
来源：
Epigenetics & Chromatin
摘要：
组蛋白去乙酰化酶（HDACs）和赖氨酸特异性脱甲基酶1（LSD1）是表观遗传癌症治疗的有吸引力的靶点。这两种酶之间存在密切的相互作用。HDACs抑制剂与LSD1抑制剂联合治疗在多种类型的癌症中显示出协同的抗癌效果。在此，我们描述了化合物5e的发现，它是一种高效的HDACs抑制剂（HDAC1/2/6/8；IC50=2.07/4.71/2.40/107 nM），具有抗LSD1作用的能力（IC50=1.34 μM）。化合物5e在多种癌细胞系中表现出显著的抗增殖活性。5e有效地诱导了MGC-803和HCT-116癌细胞的线粒体凋亡，阻止了细胞迁移和侵袭，并在肝微粒体稳定性和SD大鼠中表现出可接受的药物动力学参数。更重要的是，给予口服化合物5e在MGC-803（TGI = 71.5％）和HCT-116（TGI = 57.6％）移植瘤模型中展现了比SAHA更高的抗肿瘤疗效，且耐受性良好。该研究提供了一种对HDACs和LSD1具有双重抑制活性的新型引导化合物，以进一步开发用于实体瘤治疗的表观遗传药物。还需要进一步优化以提高LSD1活性，以实现在LSD1和HDACs上平衡的双重抑制剂。Copyright © 2023 Elsevier Masson SAS. All rights reserved.
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.Copyright © 2023 Elsevier Masson SAS. All rights reserved.