| Literature DB >> 31821784 |
Andrei V Krivtsov1, Kathryn Evans2, Jayant Y Gadrey1, Benjamin K Eschle1, Charlie Hatton1, Hannah J Uckelmann1, Kenneth N Ross1, Florian Perner1, Sarah N Olsen1, Tara Pritchard2, Lisa McDermott2, Connor D Jones2, Duohui Jing2, Ali Braytee3, Diego Chacon3, Eric Earley4, Brian M McKeever5, David Claremon6, Andrew J Gifford7, Heather J Lee8, Beverly A Teicher9, John E Pimanda10, Dominik Beck3, Jennifer A Perry1, Malcolm A Smith9, Gerard M McGeehan11, Richard B Lock2, Scott A Armstrong12.
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.Entities:
Keywords: DOT1L; MLL fusion; Menin inhibitor; acute myeloid leukemia (AML); chromatin remodeling; infant B cell acute lymphoblastic leukemia (B-ALL); leukemia
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Year: 2019 PMID： 31821784 PMCID： PMC7227117 DOI： 10.1016/j.ccell.2019.11.001
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743