6PKC

Inhibition of Human Menin by VTP-50469

6PKC の概要

• エントリーDOI: 10.2210/pdb6pkc/pdb
• 分子名称: Menin,Menin, 5-fluoro-2-({4-[7-({trans-4-[(methylsulfonyl)amino]cyclohexyl}methyl)-2,7-diazaspiro[3.5]nonan-2-yl]pyrimidin-5-yl}oxy)-N,N-di(propan-2-yl)benzamide (3 entities in total)
• 機能のキーワード: human menin, transcription, inhibitor complex, vtp-50469
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 110996.01

構造登録者

McKeever, B.M.,Chen, G.,Van Orton, R. (登録日: 2019-06-29, 公開日: 2019-12-18, 最終更新日: 2023-10-11)

主引用文献

Krivtsov, A.V.,Evans, K.,Gadrey, J.Y.,Eschle, B.K.,Hatton, C.,Uckelmann, H.J.,Ross, K.N.,Perner, F.,Olsen, S.N.,Pritchard, T.,McDermott, L.,Jones, C.D.,Jing, D.,Braytee, A.,Chacon, D.,Earley, E.,McKeever, B.M.,Claremon, D.,Gifford, A.J.,Lee, H.J.,Teicher, B.A.,Pimanda, J.E.,Beck, D.,Perry, J.A.,Smith, M.A.,McGeehan, G.M.,Lock, R.B.,Armstrong, S.A.
A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia.
Cancer Cell, 36:660-673.e11, 2019

PubMed 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.

PubMed: 31821784
DOI: 10.1016/j.ccell.2019.11.001

実験手法

X-RAY DIFFRACTION (1.9 Å)