Novel dual LSD1/HDAC6 inhibitors for the treatment of multiple myeloma
Novel dual LSD1/HDAC6 inhibitors for the treatment of multiple myeloma
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DOI：
10.1016/j.bmcl.2020.127763
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发表时间：
2021-01-08
影响因子：
2.7
通讯作者：
Rajagopal, Sridharan
中科院分区：
文献类型：
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作者：
Sadhu, M. Naveen;Sivanandhan, Dhanalakshmi;Rajagopal, Sridharan
赖氨酸特异性去甲基化酶1 （LSD1）和HDAC6是与包括癌症在内的几种疾病相关的表观遗传蛋白，联合抑制这些蛋白可能对治疗AML、MM和实体瘤等一些癌症非常有益。多发性骨髓瘤（MM）是一种具有挑战性的癌症，复发率快，需要新的治疗方案。我们设计并开发了新的LSD1和HDAC6选择性双抑制剂靶向MM。我们的双抑制剂化合物1在多种MM细胞系中表现出优异的效力。在MM.1S异种移植模型中，化合物1口服给药的疗效优于单药LSD1和HDAC6抑制剂，且耐受性良好。对该分子在其他癌症中的作用的进一步评估正在进行中。
Lysine specific demethylase 1 (LSD1) and HDAC6 are epigenetic proteins associated with several diseases, including cancer and combined inhibition of these proteins could be highly beneficial in treating some cancers such as AML, MM and solid tumors. Multiple myeloma (MM) is a challenging cancer with fast relapse rate where novel treatment options are the need of the hour. We have designed and developed novel, LSD1 and HDAC6 selective dual inhibitors to target MM. Our dual inhibitor compound 1 shows superior potency in multiple MM cell lines. In MM.1S xenograft model compound 1 shows superior efficacy compared to single agent LSD1 and HDAC6 inhibitors by oral administration and is well tolerated. Further evaluation of the molecule in other cancers is in progress.