77103-47-0Relevant articles and documents
Allosteric Inhibition of the Tumor-Promoting Interaction between Exon 2–Depleted Splice Variant of Aminoacyl–Transfer RNA Synthetase-Interacting Multifunctional Protein 2 and Heat Shock Protein 70
Huddar, Srigouri,Kim, Dae Gyu,Kim, Minkyoung,Kim, Sunghoon,Kong, Jiwon,Lee, Kyeong,Lee, Seungbeom,Lee, Sunkyung,Lee, Yuno,Lim, Semi,Park, Chul Min,Suh, Young-Ger
, p. 358 - 371 (2021/12/29)
Although protein-protein interactions (PPIs) have emerged as an attractive therapeutic target space, the identification of chemicals that effectively inhibit PPIs remains challenging. Here, we identified through library screening a chemical probe (compound 1) that can inhibit the tumor-promoting interaction between the oncogenic factor exon 2–depleted splice variant of aminoacyl–transfer RNA synthetase-interacting multifunctional protein 2 (AIMP2-DX2) and heat shock protein 70 (HSP70). We found that compound 1 binds to the N-terminal subdomain of glutathione S-transferase (GST-N) of AIMP2-DX2, causing a direct steric clash with HSP70 and an intramolecular interaction between the N-terminal flexible region and the GST-N of AIMP2-DX2, which induces masking of the HSP70 binding region during molecular dynamics and mutation studies. Compound 1 thus interferes with the AIMP2-DX2 and HSP70 interaction and suppresses the growth of cancer cells that express high levels of AIMP2-DX2 in vitro and in preliminary in vivo experiment. This work provides an example showing that allosteric conformational changes induced by chemicals can be a way to control pathologic PPIs. SIGNIFICANCE STATEMENT Compound 1 is a promising protein-protein interaction inhibitor between AIMP2-DX2 and HSP70 for cancer therapy by the mechanism with allosteric modulation as well as competitive binding. It seems to induce allosteric conformational change of AIMP2-DX2 proteins and direct binding clash between AIMP2-DX2 and HSP70. The compound reduced the level of AIMP2-DX2 in ubiquitin-dependent manner via suppression of binding between AIMP2-DX2 and HSP70 and suppressed the growth of cancer cells highly expressing AIMP2-DX2 in vitro and in preliminary in vivo experiment.
Synthesis of new metallomesogens based on 3-ketoesters
Kovganko,Kovganko
, p. 1556 - 1562 (2013/10/22)
Ethyl 3-(4-hydroxyphenyl)-3-ketopropionate was synthesized by acylation of acetoacetic ester with 4-acetoxybenzoyl chloride, followed by cleavage of aroylacetoacetic ester and hydrolysis of the protecting acetate group. Further esterification of the pheno
Identification, design and biological evaluation of bisaryl quinolones targeting Plasmodium falciparum type II NADH:Quinone oxidoreductase (PfNDH2)
Pidathala, Chandrakala,Amewu, Richard,Pacorel, Bénédicte,Nixon, Gemma L.,Gibbons, Peter,Hong, W. David,Leung, Suet C.,Berry, Neil G.,Sharma, Raman,Stocks, Paul A.,Srivastava, Abhishek,Shone, Alison E.,Charoensutthivarakul, Sitthivut,Taylor, Lee,Berger, Olivier,Mbekeani, Alison,Hill, Alasdair,Fisher, Nicholas E.,Warman, Ashley J.,Biagini, Giancarlo A.,Ward, Stephen A.,O'Neill, Paul M.
supporting information; experimental part, p. 1831 - 1843 (2012/05/04)
A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure-activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl) quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC50 against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc1, and studies to determine the potential advantage of this dual-targeting effect are in progress.
