KPT‐330 inhibitor of CRM1 (XPO1)‐mediated nuclear export has selective anti‐leukaemic activity in preclinical models of T‐cell acute lymphoblastic leukaemia and acute myeloid leukaemia

Summary This study explored the anti‐leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 ( CRM 1, also termed XPO 1). We found that these novel CRM 1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T ‐cell acute lymphoblastic leukaemia ( T ‐ ALL ) cell lines representing different molecular subtypes of the disease. To assess in vivo anti‐leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T ‐ ALL MOLT ‐4 cells, which harbour activating mutations of NOTCH 1 and NRAS as well as loss of function of the CDKN 2 A , PTEN and TP 53 tumour suppressors and express a high level of oncogenic transcription factor TAL 1 . Importantly, we examined the in vivo anti‐leukaemic efficacy of the clinical SINE compound KPT ‐330 against T‐ ALL and acute myeloid leukaemia ( AML ) cells. These studies demonstrated striking in vivo activity of KPT ‐330 against T ‐ ALL and AML cells, with little toxicity to normal murine haematopoietic cells. Taken together, our results show that SINE CRM 1 antagonists represent promising ‘first‐in‐class’ drugs with a novel mechanism of action and wide therapeutic index, and imply that drugs of this class show promise for the targeted therapy of T ‐ ALL and AML .