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Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-12-13 , DOI: 10.1021/acsmedchemlett.9b00471 Andrew E Shouksmith 1 , Justyna M Gawel 1 , Nabanita Nawar 1 , Diana Sina 1 , Yasir S Raouf 1 , Shazreh Bukhari 1 , Liying He 1 , Alexandra E Johns 1 , Pimyupa Manaswiyoungkul 1 , Olasunkanmi O Olaoye 1 , Aaron D Cabral 1 , Abootaleb Sedighi 1 , Elvin D de Araujo 1 , Patrick T Gunning 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-12-13 , DOI: 10.1021/acsmedchemlett.9b00471 Andrew E Shouksmith 1 , Justyna M Gawel 1 , Nabanita Nawar 1 , Diana Sina 1 , Yasir S Raouf 1 , Shazreh Bukhari 1 , Liying He 1 , Alexandra E Johns 1 , Pimyupa Manaswiyoungkul 1 , Olasunkanmi O Olaoye 1 , Aaron D Cabral 1 , Abootaleb Sedighi 1 , Elvin D de Araujo 1 , Patrick T Gunning 1
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The HDAC inhibitor 4-tert-butyl-N-(4-(hydroxycarbamoyl)phenyl)benzamide (AES-350, 51) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, AES-135, compound 51 demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound 51 also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that 51 dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
中文翻译：
I / IIb类选择性HDAC抑制剂在急性髓样白血病中具有口服生物利用度和治疗功效。
HDAC抑制剂4-叔丁基-N-（4-（羟基氨基甲酰基）苯基）苯甲酰胺（AES-350，51）被确定为治疗急性髓细胞白血病（AML），具有侵袭性的恶性肿瘤的有希望的临床前候选药物。 5年生存率仅为24％。通过筛选源自先前发现的新型HDAC抑制剂AES-135的低分子量类似物，化合物51显示出更高的HDAC同工型选择性，MV4-11细胞中更高的细胞毒性，改善的治疗范围以及通过细胞和细胞的更有效吸收脂质膜。与SAHA相比，化合物51在小鼠模型中还具有改善的口服生物利用度。广泛的实验，包括FACS，ELISA和Western blotting，
更新日期：2019-12-30
中文翻译：
I / IIb类选择性HDAC抑制剂在急性髓样白血病中具有口服生物利用度和治疗功效。
HDAC抑制剂4-叔丁基-N-（4-（羟基氨基甲酰基）苯基）苯甲酰胺（AES-350，51）被确定为治疗急性髓细胞白血病（AML），具有侵袭性的恶性肿瘤的有希望的临床前候选药物。 5年生存率仅为24％。通过筛选源自先前发现的新型HDAC抑制剂AES-135的低分子量类似物，化合物51显示出更高的HDAC同工型选择性，MV4-11细胞中更高的细胞毒性，改善的治疗范围以及通过细胞和细胞的更有效吸收脂质膜。与SAHA相比，化合物51在小鼠模型中还具有改善的口服生物利用度。广泛的实验，包括FACS，ELISA和Western blotting，
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