| Autor: |
Xu S, Aguilar A, Huang L, Xu T, Zheng K, McEachern D, Przybranowski S, Foster C, Zawacki K, Liu Z, Chinnaswamy K, Stuckey J, Wang S |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2020 May 14; Vol. 63 (9), pp. 4997-5010. Date of Electronic Publication: 2020 Apr 27. |
| DOI: |
10.1021/acs.jmedchem.0c00547 |
| Abstrakt: |
Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 ( 16 ) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
