6PKC

Inhibition of Human Menin by VTP-50469

Summary for 6PKC

• Entry DOI: 10.2210/pdb6pkc/pdb
• Descriptor: 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)
• Functional Keywords: human menin, transcription, inhibitor complex, vtp-50469
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 110996.01

Authors

McKeever, B.M.,Chen, G.,Van Orton, R. (deposition date: 2019-06-29, release date: 2019-12-18, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.9 Å)