There is still a great demand in the clinic for the drugs which can overcome a variety of imatinib resistant ABL mutants. Starting from a type I inhibitor axitinib, which has been reported to overcome ABL-T315I mutant induced resistance, through a structure guided drug design approach and binding mode switch strategy, we have discovered a novel type II ABL inhibitor 24 (CHMFL-ABL-121), which significantly improved the inhibitory activity against ABL wt and a broad spectrum of mutants including the most prevalent imatinib-resistant gatekeeper mutant T315I. 24 exhibited IC₅₀ values of 2 nM and 0.2 nM against purified inactive ABL wt and T315I kinase protein respectively and inhibited the proliferation of the established CML cell lines with GI₅₀ at single digit nM. In cellular context, 24 strongly affected BCR-ABL mediated signaling pathways and induced apoptosis as well as arrested cell cycle at G0/G1 phase. In the in vivo study, 50 mg/kg/day dosage of 24 displayed TGI of 52% in the TEL-ABLT315I-BaF3 cell inoculated allograft mouse model without obvious toxicity.

在临床上仍然需要能够克服各种对伊马替尼耐药的ABL突变体的药物。从一种据报道可克服ABL-T315I突变体诱导的耐药性的I型抑制剂阿西替尼开始，通过结构指导药物设计方法和结合模式转换策略，我们发现了一种新型的II型ABL抑制剂24（CHMFL-ABL-121 ），从而显着改善了对ABL wt的抑制活性以及包括最流行的伊马替尼耐药性看门人突变体T315I在内的多种突变体。24对纯化的非活性ABL wt和T315I激酶蛋白分别显示2nM和0.2nM的IC ₅₀值，并用GI ₅₀抑制已建立的CML细胞系的增殖单位为nM。在细胞环境中，有24种强烈影响BCR-ABL介导的信号通路，并诱导了细胞凋亡以及G0 / G1期的细胞周期停滞。在体内研究中，在TEL-ABLT315I-BaF3细胞接种的同种异体移植小鼠模型中，以24 mg的50 mg / kg / day剂量显示TGI为52％，而没有明显的毒性。