7520-94-7Relevant articles and documents
Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers
Koundinya, Malvika,Sudhalter, Judith,Courjaud, Albane,Lionne, Bruno,Touyer, Gaetan,Bonnet, Luc,Menguy, Isabelle,Schreiber, Isabelle,Perrault, Christelle,Vougier, Stephanie,Benhamou, Brigitte,Zhang, Bailin,He, Timothy,Gao, Qiang,Gee, Patricia,Simard, Daniel,Castaldi, M. Paola,Tomlinson, Ronald,Reiling, Stephan,Barrague, Matthieu,Newcombe, Richard,Cao, Hui,Wang, Yanjun,Sun, Fangxian,Murtie, Joshua,Munson, Mark,Yang, Eric,Harper, David,Bouaboula, Monsif,Pollard, Jack,Grepin, Claudine,Garcia-Echeverria, Carlos,Cheng, Hong,Adrian, Francisco,Winter, Christopher,Licht, Stuart,Cornella-Taracido, Ivan,Arrebola, Rosalia,Morris, Aaron
, p. 705 - 11,717 (2018)
Activating KRAS mutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival of KRAS mutant cells, but their application to drug discovery has proven challenging, possibly due in part to a failure of monolayer cultures to model tumor biology. Here, we report the results of a high-throughput synthetic lethal screen for small molecules that selectively inhibit the growth of KRAS mutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the most KRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH). DHODH inhibition is shown to perturb multiple metabolic pathways. In vivo preclinical studies demonstrate strong antitumor activity upon DHODH inhibition in a pancreatic tumor xenograft model. Koundinya et al. show that inhibitors of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase selectively inhibit the growth of KRAS mutant cell lines. Differential sensitivity of the mutant lines correlates with differential effects of the inhibitors on primary energy metabolism and glutamine levels, and the inhibitors synergize with some clinically used anticancer agents.
Novel cyanothiouracil and cyanothiocytosine derivatives as concentration-dependent selective inhibitors of U87MG glioblastomas: Adenosine receptor binding and potent PDE4 inhibition
Sahin, Zafer,Biltekin, Sevde Nur,Yurttas, Leyla,Berk, Barkin,?zhan, Ya?mur,Sipahi, Hande,Gao, Zhan-Guo,Jacobson, Kenneth A.,Demirayak, ?eref
, (2021/01/12)
Thiouracil and thiocytosine are important heterocyclic pharmacophores having pharmacological diversity. Antitumor and antiviral activity is commonly associated with thiouracil and thiocytosine derivatives, which are well known fragments for adenosine receptor affinity with many associated pharmacological properties. In this respect, 33 novel compounds have been synthesized in two groups: 24 thiouracil derivatives (4a-x) and 9 thiocytosine derivatives (5a-i). Antitumor activity of all the compounds was determined in the U87 MG glioblastoma cell line. Compound 5e showed an anti-proliferative IC50 of 1.56 μM, which is slightly higher activity than cisplatin (1.67 μM). The 11 most active compounds showed no signficant binding to adenosine A1, A2A or A2B receptors at 1 μM. Brain tumors express high amounts of phosphodiesterases. Compounds were tested for PDE4 inhibition, and 5e and 5f showed the best potency (5e: 3.42 μM; 5f: 0.97 μM). Remakably, those compounds were also the most active against U87MG. However, the compounds lacked a cytotoxic effect on the HEK293 healthy cell line, which encourages further investigation.
Potent ribonucleotide reductase inhibitors: Thiazole-containing thiosemicarbazone derivatives
Ertas, Merve,Sahin, Zafer,Bulbul, Emre F.,Bender, Ceysu,Biltekin, Sevde N.,Berk, Barkin,Yurttas, Leyla,Nalbur, Aysu M.,Celik, Hayati,Demirayak, ?eref
, (2019/11/03)
The antioxidant, antimalarial, antibacterial, and antitumor activities of thiosemicarbazones have made this class of compounds important for medicinal chemists. In addition, thiosemicarbazones are among the most potent and well-known ribonucleotide reductase inhibitors. In this study, 24 new thiosemicarbazone derivatives were synthesized, and the structures and purity of the compounds were determined by IR, 1H NMR, 13C NMR, mass spectroscopy, and elemental analysis. The IC50 values of these 24 compounds were determined with an assay for ribonucleotide reductase inhibition. Compounds 19, 20, and 24 inhibited ribonucleotide reductase enzyme activity at a higher level than metisazone as standard. The cytotoxic effects of these compounds were measured on the MCF7 (human breast adenocarcinoma) and HEK293 (human embryonic kidney) cell lines. Similarly, compounds 19, 20, and 24 had a selective effect on the MCF7 and HEK293 cell lines, killing more cancer cells than cisplatin as standard. The compounds (especially 19, 20, and 24 as the most active ones) were then subjected to docking experiments to identify the probable interactions between the ligands and the enzyme active site. The complex formation was shown qualitatively. The ADME (absorption, distribution, metabolism, and excretion) properties of the compounds were analyzed using in-silico techniques.
