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Cancer Cell ; 36(6): 660-673.e11, 2019 12 09.
Article in English | MEDLINE | ID: mdl-31821784

ABSTRACT

Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.


Subject(s)
Chromatin/drug effects , Gene Expression Regulation, Leukemic/drug effects , Leukemia, Myeloid, Acute/drug therapy , Proto-Oncogene Proteins/drug effects , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Chromatin/genetics , Gene Expression Regulation, Leukemic/genetics , Gene Rearrangement/drug effects , Gene Rearrangement/genetics , Humans , Leukemia, Myeloid, Acute/genetics , Mice , Proto-Oncogene Proteins/genetics , Transcription Factors/drug effects , Transcription Factors/genetics
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