Humanized mice enable accurate preclinical evaluation of MCL-1 inhibitors destined for clinical use.

Myeloid cell leukemia-1 (MCL-1) is a prosurvival B-cell lymphoma 2 (BCL-2) family member required for the sustained growth of many cancers. Recently, a highly specific MCL-1 inhibitor, S63845, showing sixfold higher affinity to human compared with mouse MCL-1, has been described. To accurately test efficacy and tolerability of this BH3-mimetic (BH3-only protein mimetic) drug in preclinical cancer models, we developed a humanized () mouse strain in which MCL-1 was replaced with its human homolog. mice are phenotypically indistinguishable from wild-type mice but are more sensitive to the MCL-1 inhibitor S63845. Importantly, nontransformed cells and lymphomas from mice are more sensitive to S63845 in vitro than their control counterparts. When lymphoma cells were transplanted into mice, treatment with S63845 alone or alongside cyclophosphamide led to long-term remission in ∼60% or almost 100% of mice, respectively. These results demonstrate the potential of our mouse model for testing MCL-1 inhibitors, allowing precise predictions of efficacy and tolerability for clinical translation.