Abstract

BCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABL^T315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC₅₀ values of < 0.5 nM, and 9 nM against BCR-ABL^WT and BCR-ABL^T315I, respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC₅₀ values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI₅₀ < 10 nM, TGI = 154 nM). In addition, AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation.

摘要

BCR-ABL 抑制是治疗慢性粒细胞白血病 (CML) 的有效治疗方法。在此，我们报告发现AKE-72 (5)是一种二芳基酰胺 3-氨基吲唑，可作为有效的泛 BCR-ABL 抑制剂，包括伊马替尼耐药突变体 T315I。基于我们之前报道的吲唑I，设计了一系列集中的化合物4a、4b和5，以提高其 BCR-ABL ^T315I抑制活性。用特有的尾部(4-乙基哌嗪-1-基)甲基取代I的吗啉部分得到5(AKE-72)，其针对BCR-ABL ^WT和BCR-ABL ^T315I的IC ₅₀值<0.5nM，并且为9nM ，分别。此外，AKE-72有效抑制了一组其他临床上重要的突变体，IC ₅₀值为个位数。AKE-72对 K-562 细胞系具有显着的抗白血病活性（GI ₅₀ < 10 nM，TGI = 154 nM）。此外，AKE-72强烈抑制表达天然 BCR-ABL 或其 T315I 突变体的 Ba/F3 细胞的增殖。总体而言，AKE-72可能作为治疗 CML 的有前途的候选药物，包括那些含有 T315I 突变的 CML。