288617-76-5Relevant articles and documents
PEPTIDOMIMETIC INHIBITORS OF THE WDR5-MLL INTERACTION
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Paragraph 0240; 0244; 0245, (2018/12/13)
The present disclosure provides compounds represented by Formula I: and the pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3a, R3b, R4a, R4b, R5a, and R5b are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat a condition, disease, or disorder responsive to inhibition of the WDR5 interaction with its binding partners including, but not limited to, the WDR5-MLL protein-protein interaction.
Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)-Mixed Lineage Leukemia (MLL) Protein-Protein Interaction
Karatas, Hacer,Li, Yangbing,Liu, Liu,Ji, Jiao,Lee, Shirley,Chen, Yong,Yang, Jiuling,Huang, Liyue,Bernard, Denzil,Xu, Jing,Townsend, Elizabeth C.,Cao, Fang,Ran, Xu,Li, Xiaoqin,Wen, Bo,Sun, Duxin,Stuckey, Jeanne A,Lei, Ming,Dou, Yali,Wang, Shaomeng
, p. 4818 - 4839 (2017/06/28)
We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5-mixed lineage leukemia (MLL) protein-protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC50 value of 0.90 nM (Ki value 50 value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis for their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5-MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.
Influence of α-methylation in constructing stapled peptides with olefin metathesis
Zhang, Qingzhou,Shi, Xiaodong,Jiang, Yanhong,Li, Zigang
, p. 7621 - 7626 (2014/12/11)
Ring-closing metathesis is commonly utilized in peptide macro-cyclization. The influence of α-methylation of the amino acids bearing the olefin moieties has never been systematically studied. In this report, controlled reactions unambiguously indicate that α-methylation at the N-terminus of the metathesis sites is crucial for this reaction to occur. Also, we first elucidated that the E-isomers of stapled peptides are significantly more helical than the Z-isomers.
Design of cell-permeable stapled peptides as HIV-1 integrase inhibitors
Long, Ya-Qiu,Huang, Shao-Xu,Zawahir, Zahrah,Xu, Zhong-Liang,Li, Huiyuan,Sanchez, Tino W.,Zhi, Ying,De Houwer, Stephanie,Christ, Frauke,Debyser, Zeger,Neamati, Nouri
, p. 5601 - 5612 (2013/07/26)
HIV-1 integrase (IN) catalyzes the integration of viral DNA into the host genome, involving several interactions with the viral and cellular proteins. We have previously identified peptide IN inhibitors derived from the α-helical regions along the dimeric interface of HIV-1 IN. Herein, we show that appropriate hydrocarbon stapling of these peptides to stabilize their helical structure remarkably improves the cell permeability, thus allowing inhibition of the HIV-1 replication in cell culture. Furthermore, the stabilized peptides inhibit the interaction of IN with the cellular cofactor LEDGF/p75. Cellular uptake of the stapled peptide was confirmed in four different cell lines using a fluorescein-labeled analogue. Given their enhanced potency and cell permeability, these stapled peptides can serve as not only lead IN inhibitors but also prototypical biochemical probes or nanoneedles for the elucidation of HIV-1 IN dimerization and host cofactor interactions within their native cellular environment.
