KIF11 and its inhibitor SB-743921 inhibit acute myeloid leukaemia (AML) by blocking the cell cycle
Acute myeloid leukaemia (AML) is a highly heterogeneous haematological malignancy with limited prognostic improvement despite evolving therapeutic strategies.KIF11 is a member of the kinesin family and a microtubule-associated motility protein that plays a key role in spindle dynamics during cellular mitosis and is overexpressed in leukaemias including AML. Studies have shown that inhibition of KIF11 leads to spindle pole collapse, which prevents chromosome segregation and leads to cell death; this identifies KIF11 as a potential therapeutic target.SB-743921, a novel selective inhibitor of KIF11, has shown anti-tumour activity in a variety of cancers, including breast, lung, and cholangiocarcinoma. Our study shows that SB-743921 can effectively inhibit the proliferation of AML cells and induce cell cycle arrest, thereby hindering tumour growth. In vitro experiments showed that SB-743921 exhibited significant cytotoxicity against several AML cell lines, and its IC50 value indicated that these cells were very sensitive to SB-743921. Further in vivo studies in AML mouse models treated with SB-743921 showed that the drug significantly delayed tumour progression while prolonging survival with minimal toxic side effects. In addition, RNA sequencing analysis showed that SB-743921 inhibited tumour cell proliferation by down-regulating key signalling pathways, including MYC, E2F and G2M. These findings suggest that KIF11 plays a crucial role in the onset and progression of AML. As its inhibitor, SB-743921 has significant anti-tumour effects and is an innovative targeted agent for the treatment of AML. This discovery provides new insights into potential clinical applications for the treatment of this challenging malignancy. Overall design: mRNA profiles of CMK cells treated with 4nmol SB-743921 or not for 24 h were generated by RNA sequencing, in double, using Illumina NovaSeq6000.