An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
We used classical linear and microwave-assisted synthesis methods to prepare novel N-substituted, benzimidazole-derived acrylonitriles with antiproliferative activity against several cancer cells in vitro. The most potent systems showed pronounced activity against all tested hematological cancer cell lines, with favorable selectivity towards normal cells. The selection of lead compounds was also tested in vitro for tubulin polymerization inhibition as a possible mechanism of biological action. A combination of docking and molecular dynamics simulations confirmed the suitability of the employed organic skeleton for the design of antitumor drugs and demonstrated that their biological activity relies on binding to the colchicine binding site in tubulin. In addition, it also underlined that higher tubulin affinities are linked with (i) bulkier alkyl and aryl moieties on the benzimidazole nitrogen and (ii) electron-donating substituents on the phenyl group that allow deeper entrance into the hydrophobic pocket within the tubulin’s β-subunit, consisting of Leu255, Leu248, Met259, Ala354, and Ile378 residues.
Abstract Two novel series of human immunodeficiency virus‐1 ( HIV ‐1) non‐nucleoside reverse transcriptase inhibitors ( NNRTI s) bearing a thiophene[3,2‐ d ]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against the wild‐type ( WT ) HIV ‐1 strain in MT ‐4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV ‐1. Compound 7 ( EC 50 = 0.014, 0.031 μM) achieved the most potent activity against the two mutants, being more effective than that of nevirapine ( NVP , EC 50 = 7.572, 0.190 μM) and comparable to that of etravirine ( ETV , EC 50 = 0.004, 0.014 μM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization.
Abstract Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports a wide variety of different cargo proteins including tumor suppressors out of the cell's nucleus. Inhibition of XPO1 function consequently restores nuclear localization of these proteins and is a promising therapeutic strategy for cancer. Selective inhibitor of nuclear export (SINE) compounds are inhibitors of the XPO1-mediated nuclear export with potent anti-cancer activity. The oral clinical candidate SINE selinexor (KPT-330) is currently in Phase-II/IIb clinical trials and demonstrated remission in patients as a single agent or in combination therapy in trials for pre-treated, relapsed and refractory hematological and solid tumor malignancies. The drug is generally well tolerated when dosed every other day 1-3 times a week. However, XPO1 inhibitors with improved tolerability allowing more frequent dosing can be expected to have a substantial clinical benefit. Here we present the anti-leukemic activity of a second-generation XPO1 inhibitor KPT-8602 with improved tolerability allowing for a daily dosing regimen. First, its anti-XPO1 activity was assessed; KPT-8602 potently inhibited the XPO1-mediated nuclear protein export at nanomolar concentrations and it blocked the interaction of XPO1 with cargo protein. KPT-8602 also induced potent cytotoxicity on a panel of T-ALL and B-ALL cell lines. Cytotoxicity correlated with the induction of caspase-dependent apoptosis and the nuclear accumulation of p53 as well as the subsequent induction of p53 response. To further investigate the mechanism of action of KPT-8602 we applied CRISPR/Cas9 to introduce a Cys528Ser mutation in the XPO1 gene of four different leukemia cell lines. Mutant cells were over 100 times resistant to KPT-8602. In addition, drug-target interaction was confirmed by pull-down of wild-type XPO1 protein out of cells using biotinylated KPT-8602 while it was unable to pull down mutated XPO1C528S out of mutant cells. These results illustrate the highly specific interaction of the drug for its target and prove that the anti-leukemic activity of KPT-8602 is caused by inhibition of XPO1. To examine the anti-leukemic activity of KPT-8062 in vivo, mice engrafted with patient-derived T-cell acute lymphoblastic leukemia were treated with KPT-8602 or placebo. Mice were daily treated by oral gavage for 3 weeks. Treatment with KPT-8602 led to a significant reduction of leukemia cell numbers in blood as measured by weekly blood counts, without affecting normal erythropoiesis. Animals treated with KPT-8602 had prolonged survival compared to placebo treated animals. KPT-8602 also showed potent anti-leukemia activity in a mouse T-ALL leukemia model. In conclusion, KPT-8062 is a second-generation XPO1 inhibitor with high specificity for its target and with potent anti-ALL activity. It displays better tolerability as compared to the first-generation SINE selinexor allowing it for daily dosing resulting in effective anti-ALL activity in in vivo PDX models warranting further evaluation of this new drug in patients. As such, in January 2016 a phase I/II study with KPT-8602 has been initiated. Citation Format: Dirk Daelemans, Jasper Edgar Neggers, Jolien De Bie, Maarten Jacquemyn, Astrid D’Hoore, Els Vanstreels, Erkan Baloglu, Yosef Landesman, Sharon Shacham, William Senapedis, Antonis Dagklis, Thomas Vercruysse, Jan Cools. KPT-8602 is a second-generation XPO1 inhibitor with improved in vivo tolerability that demonstrates potent acute lymphoblastic leukemia activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-210.
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