Department of Biochemistry and Molecular Biology , Indiana University School of Medicine , Indianapolis , Indiana 46202 , United States.
Department of Materials Science Engineering , University of Michigan , Ann Arbor , Michigan 48109 , United States.
J Med Chem. 2018 Oct 11;61(19):8754-8773. doi: 10.1021/acs.jmedchem.8b00930. Epub 2018 Sep 28.
Aldehyde dehydrogenase (ALDH) activity is commonly used as a marker to identify cancer stem-like cells. The three ALDH1A isoforms have all been individually implicated in cancer stem-like cells and in chemoresistance; however, which isoform is preferentially expressed varies between cell lines. We sought to explore the structural determinants of ALDH1A isoform selectivity in a series of small-molecule inhibitors in support of research into the role of ALDH1A in cancer stem cells. An SAR campaign guided by a cocrystal structure of the HTS hit CM39 (7) with ALDH1A1 afforded first-in-class inhibitors of the ALDH1A subfamily with excellent selectivity over the homologous ALDH2 isoform. We also discovered the first reported modestly selective single isoform 1A2 and 1A3 inhibitors. Two compounds, 13g and 13h, depleted the CD133 putative cancer stem cell pool, synergized with cisplatin, and achieved efficacious concentrations in vivo following IP administration. Compound 13h additionally synergized with cisplatin in a patient-derived ovarian cancer spheroid model.
醛脱氢酶（ALDH）活性通常被用作鉴定癌症干细胞样细胞的标志物。三种 ALDH1A 同工型都分别与癌症干细胞样细胞和化疗耐药性有关；然而，同工型的优先表达在细胞系之间有所不同。我们试图在一系列小分子抑制剂中探索 ALDH1A 同工型选择性的结构决定因素，以支持 ALDH1A 在癌症干细胞中的作用的研究。一项基于高内涵筛选命中化合物 CM39（7）与 ALDH1A1 的共晶结构的 SAR 研究，为 ALDH1A 亚家族提供了具有良好同源 ALDH2 同工型选择性的一流抑制剂。我们还发现了首例报道的具有适度选择性的单同工型 1A2 和 1A3 抑制剂。两种化合物 13g 和 13h 耗尽了 CD133 假定的癌症干细胞池，与顺铂协同作用，并在 IP 给药后在体内达到有效的浓度。化合物 13h 还在源自患者的卵巢癌球体模型中与顺铂协同作用。
