Fig. 1
KF1601 forms stable complexes with BCR::ABL1 and BCR::ABL1T315I, inhibiting downstream signaling pathways and demonstrating potent in vivo efficacy. A KF1601 forms four hydrogen bonds with native BCR::ABL1. B KF1601 forms three hydrogen bonds with BCR::ABL1T315I. The magenta dashed lines represent hydrogen bond interactions. C Immunoblotting results shown in three panels: the left panel displays results from Ba/F3 parental cells, the middle panel displays results from Ba/F3 cells expressing native BCR::ABL1, and the right panel displays results from Ba/F3 cells expressing BCR::ABL1T315I. Ponatinib served as a positive control for BCR::ABL1T315I, and nilotinib as a negative control. KF1601 demonstrated dose-dependent inhibition of the downstream signaling pathway of BCR::ABL1 in both Ba/F3 cells expressing native BCR::ABL1 and Ba/F3 cells expressing BCR::ABL1T315I. D Dose–response curves for KF1601 in Ba/F3 cell line and IC50 values of KF1601 and imatinib. Ba/F3: Ba/F3 parental cells; Ba/F3BCR::ABL1: Ba/F3 cells expressing native BCR::ABL1; Ba/F3T315I: Ba/F3 cells expressing BCR::ABL1T315I; K562, TCCS, KOPM28: patient-derived CML cell lines with native BCR::ABL1; TCCST315I and KOPM28T315I: sublines of TCCS and KOPM28 with BCR::ABL1T315I. E Tumor growth inhibition in a CML xenograft mouse model using K562 human CML cells. Following cessation of KF1601 treatment, complete tumor regression was maintained in 3 out of 10 mice treated with 5 mg/kg of KF1601, and in all mice treated with either 10 mg/kg or 30 mg/kg of KF1601 until the end of the study. Each KF1601 treatment group was compared to the vehicle group based on the treatment day using GraphPad prism 10, with statistical significance (p < 0.0001). F Reduction in tumor burden in an orthotopic CML mouse model mice. The tumor burden in KF1601-treated groups was reduced by over 99% compared to that in the vehicle-treated group. **** p < 0.0001. G Post-treatment survival of orthotopic CML mice. In the KF1601-treated groups, the median survival time increased to 31–35 days, compared to 21 days in the vehicle-treated group. Curves were compared by Log-rank Mantel-Cox test (KF1601 25 mg/kg p < 0.001, Ponatinib 25 mg/kg, KF1601 50 mg/kg and KF1601 100 mg/kg p < 0.0001)