Lolli Marco L, Carnovale Irene M, Pippione Agnese C, Wahlgren Weixiao Y, Bonanni Davide, Marini Elisabetta, Zonari Daniele, Gallicchio Margherita, Boscaro Valentina, Goyal Parveen, Friemann Rosmarie, Rolando Barbara, Bagnati Renzo, Adinolfi Salvatore, Oliaro-Bosso Simonetta, Boschi Donatella
Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125 Turin, Italy.
Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, S-40530 Gothenburg, Sweden.
ACS Med Chem Lett. 2019 Jan 28;10(4):437-443. doi: 10.1021/acsmedchemlett.8b00484. eCollection 2019 Apr 11.
Aldo-keto reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known to inhibit AKR1C3 in a nonselective manner because of COX-off target effects. Here we designed two indomethacin analogues by proposing a bioisosteric connection between the indomethacin carboxylic acid function and either hydroxyfurazan or hydroxy triazole rings. Both compounds were found to target AKR1C3 in a selective manner. In particular, hydroxyfurazan derivative is highly selective for AKR1C3 over the 1C2 isoform (up to 90-times more) and inactive on COX enzymes. High-resolution crystal structure of its complex with AKR1C3 shed light onto the binding mode of the new inhibitors. In cell-based assays (on colorectal and prostate cancer cells), the two indomethacin analogues showed higher potency than indomethacin. Therefore, these two AKR1C3 inhibitors can be used to provide further insight into the role of AKR1C3 in cancer.
醛糖酮还原酶1C3（AKR1C3）因其在抗癌治疗耐药性中的作用，成为药物设计中一个颇具吸引力的靶点。已知几种非甾体抗炎药，如吲哚美辛，由于环氧化酶（COX）脱靶效应，会以非选择性方式抑制AKR1C3。在此，我们通过在吲哚美辛羧酸官能团与羟基呋咱或羟基三唑环之间建立生物电子等排连接，设计了两种吲哚美辛类似物。发现这两种化合物均以选择性方式靶向AKR1C3。特别是，羟基呋咱衍生物对AKR1C3的选择性远高于1C2亚型（高达90倍以上），且对COX酶无活性。其与AKR1C3复合物的高分辨率晶体结构揭示了新抑制剂的结合模式。在基于细胞的实验（针对结肠直肠癌和前列腺癌细胞）中，这两种吲哚美辛类似物显示出比吲哚美辛更高的效力。因此，这两种AKR1C3抑制剂可用于进一步深入了解AKR1C3在癌症中的作用。
