Journal article

Humanized Mcl-1 mice enable accurate pre-clinical evaluation of MCL-1 inhibitors destined for clinical use

Margs Brennan, Catherine Chang, Grant Dewson, Lin Tai, Guillaume Lessene, Andreas Strasser, Gemma Kelly, Marco Herold

Published : 2018

Abstract

SUMMARY MCL-1 is a pro-survival BCL-2 protein required for the sustained growth of many cancers. Recently a highly specific MCL-1-inhibitor, S63845, showing 6-fold higher affinity to human compared to mouse MCL-1 has been described. To accurately test efficacy and tolerability of this BH3 mimetic drug in pre-clinical cancer models, we developed a humanized Mcl-1 (huMcl-1) mouse in which MCL-1 was replaced with its human homologue. HuMcl-1 mice are phenotypically indistinguishable from wild-type mice but are more sensitive to MCL-1 inhibition. Importantly, non-transformed cells and lymphomas from huMcl-1;Eμ-Myc mice are more sensitive to S63845 in vitro than their control counterparts. When h..

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