Discovery of DDO-2213 as a Potent and Orally Bioavailable Inhibitor of the WDR5-Mixed Lineage Leukemia 1 Protein-Protein Interaction for the Treatment of MLL Fusion Leukemia
Discovery of DDO-2213 as a Potent and Orally Bioavailable Inhibitor of the WDR5-Mixed Lineage Leukemia 1 Protein-Protein Interaction for the Treatment of MLL Fusion Leukemia
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发现 DDO-2213 作为 WDR5-混合谱系白血病 1 蛋白质-蛋白质相互作用的有效口服生物利用抑制剂，用于治疗 MLL 融合白血病
DOI：
10.1021/acs.jmedchem.1c00091
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发表时间：
2021-06-09
影响因子：
7.3
通讯作者：
Guo, Xiaoke
中科院分区：
文献类型：
--
作者：
Chen, Weilin;Chen, Xin;Guo, Xiaoke
WDR5对混合谱系白血病1 （MLL1）复合体的稳定性和甲基转移酶活性至关重要。MLL1基因的失调与人类急性白血病有关，直接破坏WDR5-MLL1蛋白-蛋白相互作用（PPI）正成为治疗mll重排癌症的一种替代策略。在这里，我们提出了一种新的苯胺嘧啶支架用于WDR5-MLL1抑制剂。综合结构-活性分析鉴定出一种有效的抑制剂63 (DDO-2213)，在竞争荧光偏振分析中，其IC50为29 nM， K-d值为72.9 nM。化合物63选择性地抑制MLL组蛋白甲基转移酶活性和MLL易位细胞的增殖。此外，63在小鼠体内表现出良好的药代动力学特性，口服后可抑制MV4-11异种移植肿瘤的生长，首次验证了小分子靶向WDR5-MLL1 PPI的体内有效性。
WD repeat-containing protein 5 (WDR5) is essential for the stability and methyltransferase activity of the mixed lineage leukemia 1 (MLL1) complex. Dysregulation of the MLL1 gene is associated with human acute leukemias, and the direct disruption of the WDR5-MLL1 protein-protein interaction (PPI) is emerging as an alternative strategy for MLL-rearranged cancers. Here, we represent a new aniline pyrimidine scaffold for WDR5-MLL1 inhibitors. A comprehensive structure-activity analysis identified a potent inhibitor 63 (DDO-2213), with an IC50 of 29 nM in a competitive fluorescence polarization assay and a K-d value of 72.9 nM for the WDR5 protein. Compound 63 selectively inhibited MLL histone methyltransferase activity and the proliferation of MLL translocation-harboring cells. Furthermore, 63 displayed good pharmacokinetic properties and suppressed the growth of MV4-11 xenograft tumors in mice after oral administration, first verifying the in vivo efficacy of targeting the WDR5-MLL1 PPI by small molecules.