Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein?Protein Interaction [electronic resource]

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Tác giả:

Ngôn ngữ: eng

Ký hiệu phân loại: 504.5 [Unassigned]

Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2019

Mô tả vật lý: Size: p. 6015-6034 : , digital, PDF file.

Bộ sưu tập: Metadata

ID: 260009

 Inhibition of the menin-mixed lineage leukemia (MLL) protein?protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89). M-89 binds to menin with a K<
 sub>
 d<
 /sub>
  value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4
 11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC<
 sub>
 50<
 /sub>
  values of 25 and 55 nM, respectively, and demonstrates >
 100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Overall, we conclude that further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.
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