- USP30 INHIBITORS AND USES THEREOF
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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.
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- Design of Nitroso-Modified Naphthylene-Based Fluorophores as Photoactivatable Bioorthogonal Turn-On Probes
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We reported a series of nitroso-modified naphthylene-based fluorophores as novel bioorthogonal fluorescence turn-on probes. The cycloadducts from nitroso-diene Diels-Alder reaction could be either photochemically or spontaneously transformed into highly f
- Tian, Yulin,Yang, Hong,Li, Xiang,Wang, Yongcheng,Teng, Yu,Yin, Dali
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p. 3782 - 3787
(2021/05/29)
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- 5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma
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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.
- 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
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- Identification and validation of selective deubiquitinase inhibitors
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Deubiquitinating enzymes (DUBs) are a class of isopeptidases that regulate ubiquitin dynamics through catalytic cleavage of ubiquitin from protein substrates and ubiquitin precursors. Despite growing interest in DUB biological function and potential as therapeutic targets, few selective small-molecule inhibitors and no approved drugs currently exist. To identify chemical scaffolds targeting specific DUBs and establish a broader framework for future inhibitor development across the gene family, we performed high-throughput screening of a chemically diverse small-molecule library against eight different DUBs, spanning three well-characterized DUB families. Promising hit compounds were validated in a series of counter-screens and orthogonal assays, as well as further assessed for selectivity across expanded panels of DUBs. Through these efforts, we have identified multiple highly selective DUB inhibitors and developed a roadmap for rapidly identifying and validating selective inhibitors of related enzymes.
- Auld, Douglas,Buhrlage, Sara J.,Casalena, Dominick,Chan, Wai Cheung,Dhe-Paganon, Sirano,Hu, Bin,Liu, Xiaoxi,Magin, Robert S.,Marto, Jarrod A.,Roberts, Rebekka M.,Seo, Hyuk-Soo,Varca, Anthony C.,Zhu, He
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p. 1758 - 13,1771
(2021/12/20)
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- Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy
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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.
- Kluge, Arthur F.,Lagu, Bharat R.,Maiti, Pranab,Jaleel, Mahaboobi,Webb, Michael,Malhotra, Jyoti,Mallat, Ashley,Srinivas, P. Akhila,Thompson, James E.
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p. 2655 - 2659
(2018/06/25)
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- USP30 INHIBITORS
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The application relates to phenyl- or naphthylsulfonamide derivatives of the structural formula (I). The compounds are described as inhibitors of USP30 (ubiquitin specific peptidase 30) useful for the treatment of conditions involving mitochondrial defects including neurodegenerative diseases such as Alzheimer's and Parkinson's or a neoplastic disease such as leukemia.
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- Evaluation of fluorogenic aminonaphthalenesulfonamides and 6-hydrazinobenz[de]isoquinoline-1,3-diones for the detection of bacteria
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New fluorogenic enzyme substrates were synthesized by the coupling of aminonaphthalenesulfonamides or 6-hydrazinobenz[de]isoquinoline-1,3-diones with β-alanine. The 6-hydrazinobenz[de]isoquinoline-1,3-diones were also condensed with a range of aryl aldehydes to give the corresponding hydrazones. The photophysical properties of the synthesized amines and hydrazines and their amide, hydrazide and hydrazone derivatives, were examined and they were also incorporated into Columbia agar in order to determine their potential for the detection of pathogenic bacteria.
- Luo, Jia Lin,Jin, Terry,Váradi, Linda,Perry, John D.,Hibbs, David E.,Groundwater, Paul W.
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- Caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors
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HIV-1 integrase (IN) is an essential enzyme for retroviral replication and a rational target for the design of anti-AIDS drugs. In the present study, we have designed, synthesized and tested a series of caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors. Among these compounds, we found that HIV integrase inhibitory activities of compounds III-3 and III-4 were more potent than L-chicoric acid (IC50=11.8 μg/mL) and others were comparable to L-chicoric acid. Furthermore, the structure-activity relationships of these compounds were studied. The information gathered from this paper will be useful in the development and design of HIV-1 integrase inhibitors in the future.
- Xu, Yu-Wen,Zhao, Gui-Sen,Shin, Cha-Gyun,Zang, Heng-Chang,Lee, Chong-Kyo,Lee, Yong Sup
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p. 3589 - 3593
(2007/10/03)
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- Positive allosteric AMPA receptor modulators (PAARM), processes for preparing them, and their use as pharmaceutical compositions
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Compounds of formula (I) wherein R1, R2, R3, R4, R5, n, and m, are as defined herein, or an enantiomer or diastereomer thereof, or a pharmacologically acceptable salt thereof; processes for preparing these compounds, and their use in pharmaceutical compositions.
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- SULFONAMIDE ENDOTHELIN ANTAGONISTS
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Compounds of the formula STR1 inhibit endothelin, wherein: one of X and Y is N and the other is O; R is naphthyl or naphthyl substituted with R. sup.1, R 2 and R 3 ;R 1, R 2 and R 3 are each independently hydrogen; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may be substituted with Z 1, Z 2 and Z 3 ; halo; hydroxyl; cyano; nitro;--C(O)H;--C(O)R 6 ; CO 2 H;--CO 2 R 6 ;--SH;--S(O) n R 6 ;--S(O) m--OH;--S(O). sub.m--OR 6 ;--O--S(O) m--R 6 ;--O--S(O) m OH;--O--S(O) m--OR. sup.6 ;--Z 4--NR 7 R 8 ; or--Z 4--N(R. sup.11)--Z 5--NR 9 R 10 ;R 4 and R 5 are each independently hydrogen; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may be substituted with Z 1, Z 2 and Z 3 ; halo; hydroxyl; cyano; nitro;--C(O)H;--C(O)R 6 ;--CO 2 H;--CO 2 R 6 ;--SH,--S(O) n R. sup.6 ;--S(O) m--OH;--S(O) m--OR 6 ;--O--S(O) m--R. sup.6 ;--O--S(O) m OH;--O--S(O) m--OR. sup.6 ;--Z 4--NR. sup.7 R 8 ;--Z 4--N(R. sup.11)--Z 5--NR. sup.9 R 10 ; or R 4 and R 5 together are alkylene or alkenylene (either of which may be substituted with Z 1, Z 2 and Z 3), completing a 4-to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached.
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- Discovery and structure-activity relationships of sulfonamide ET(A)- selective antagonists
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Random screening of compounds in an ETA receptor binding assay led to the discovery of a class of benzenesulfonamide ligands. Optimization led to the development of 5-amino-N-(3,4-dimethyl-5-isoxazolyl)-1- naphthalenesulfonamides which were functional ant
- Stein,Floyd,Bisaha,Dickey,Girotra,Gougoutas,Kozlowski,Lee,Liu,Malley,McMullen,Mitchell,Moreland,Murugesan,Serafino,Webb,Zhang,Hunt
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p. 1344 - 1354
(2007/10/02)
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