52218-37-8Relevant articles and documents
USP30 INHIBITORS AND USES THEREOF
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, (2021/03/19)
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of USP30, and the treatment of USP30-mediated disorders.
5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma
Cong, Zhanqing,Fu, Xuhong,Geng, Meiyu,Han, Xu,Huang, Xun,Li, Chunpu,Li, Cong,Li, Jia,Li, Xingjun,Lian, Fulin,Liu, Hong,Shi, Qiongyu,Su, Mingbo,Wang, Jiang,Wang, Shuni,Wei, Rongrui,Yang, Hong,Zhang, Naixia,Zheng, Xingling,Zhou, Yubo
, (2021/06/21)
Approximately 20% of multiple myeloma (MM) are caused by a chromosomal translocation t (4; 14) that leads to the overexpression of the nuclear receptor binding SET domain-protein 2 (NSD2) histone methyltransferase. NSD2 catalyzes the methylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Using high-throughput screening (HTS) with biological analyses, a series of 5-aminonaphthalene derivatives were designed and synthesized as novel NSD2 inhibitors. Among all the prepared compounds, 9c displayed a good NSD2 inhibitory activity (IC50 = 2.7 μM) and selectivity against both SET-domain-containing and non-SET-domain-containing methyltransferases. Preliminary research indicates the inhibition mechanism of compound 9c by significantly suppressed the methylation of H3K36me2. Compound 9c specifically inhibits the proliferation of the human B cell precursor leukemia cell line RS4:11 and the human myeloma cell line KMS11 by inducing cell cycle arrest and apoptosis with little cytotoxicity. It has been reported that the anti-cancer effect of compound 9c is partly achieved by completely suppressing the transcriptional activation of NSD2-targeted genes. When administered intraperitoneally at 25 mg/kg, compound 9c suppressed the tumor growth of RS4:11 xenografts in vivo and no body weight loss was detected in the tested SCID mice.
Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy
Kluge, Arthur F.,Lagu, Bharat R.,Maiti, Pranab,Jaleel, Mahaboobi,Webb, Michael,Malhotra, Jyoti,Mallat, Ashley,Srinivas, P. Akhila,Thompson, James E.
, p. 2655 - 2659 (2018/06/25)
Mitophagy is one of the processes that cells use to maintain overall health. An E3 ligase, parkin, ubiquitinates mitochondrial proteins prior to their degradation by autophagasomes. USP30 is an enzyme that de-ubiquitinates mitochondrial proteins; therefore, inhibiting this enzyme could foster mitophagy. Herein, we disclose the structure–activity relationships (SAR) within a novel series of highly selective USP30 inhibitors. Two structurally similar compounds, MF-094 (a potent and selective USP30 inhibitor) and MF-095 (a significantly less potent USP30 inhibitor), serve as useful controls for biological evaluation. We show that MF-094 increases protein ubiquitination and accelerates mitophagy.
