| Autor: |
El-Damasy AK; Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., Kim HJ; Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea., Park JW; Supercomputing Application Center, Div. of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon, Republic of Korea., Nam Y; Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea., Hur W; Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea., Bang EK; Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea., Keum G; Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul, Republic of Korea. |
| Abstrakt: |
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 IC 50 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 IC 50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI 50 < 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. |
