Structural effects of morpholine replacement in ZSTK474 on Class I PI3K isoform inhibition: Development of novel MEK/PI3K bifunctional inhibitors was written by Van Dort, Marcian E.;Jang, Yongsoon;Bonham, Christopher A.;Heist, Kevin;Palagama, Dilrukshika S. W.;McDonald, Lucas;Zhang, Edward Z.;Chenevert, Thomas L.;Luker, Gary D.;Ross, Brian D.. And the article was included in European Journal of Medicinal Chemistry in 2022.Computed Properties of C3H9NO The following contents are mentioned in the article:
Established roles for PI3K and MAPK signaling pathways in tumorigenesis has prompted extensive research towards the discovery of small-mol. inhibitors as cancer therapeutics. However, significant compensatory regulation exists between these two signaling cascades, leading to redundancy among survival pathways. Consequently, initial clin. trials aimed at either PI3K or MEK inhibition alone have proven ineffective and highlight the need for development of targeted and innovative therapeutic combination strategies. We designed a series of PI3K inhibitor derivatives wherein a single morpholine group of the PI3K inhibitor ZSTK474 was substituted with a variety of 2-aminoethyl functional groups. Analogs with pendant hydroxyl or methoxy groups maintained low nanomolar inhibition towards PI3Kα, PI3Kγ, and PI3Kδ isoforms in contrast to those with pendant amino groups which were significantly less inhibitory. Synthesis of prototype PI3K/MEK bifunctional inhibitors (N-(2-(2-(2-(2-((4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6-morpholino-1,3,5-triazin-2-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide, N-((3-(4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6morpholino-1,3,5-triazin-2-yl)-1-hydroxy-6,9,12-trioxa-3azatetradecan-14-yl)oxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) was guided by the structure-activity data, where a MEK-targeting inhibitor was tethered directly via a short PEG linker to the triazine core of the PI3K inhibitor analogs. These compounds (N-(2-(2-(2-(2-((4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6-morpholino-1,3,5-triazin-2-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide, N-((3-(4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6morpholino-1,3,5-triazin-2-yl)-1-hydroxy-6,9,12-trioxa-3azatetradecan-14-yl)oxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) displayed nanomolar inhibition towards PI3Kα, δ, and MEK (IC50 ∼105-350 nM), and low micromolar inhibition for PI3Kβ and PI3Kγ (IC50 ∼1.5-3.9 μM) in enzymic inhibition assays. Cell viability assays demonstrated superior anti-proliferative activity for N-((3-(4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6morpholino-1,3,5-triazin-2-yl)-1-hydroxy-6,9,12-trioxa-3azatetradecan-14-yl)oxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide over N-(2-(2-(2-(2-((4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6-morpholino-1,3,5-triazin-2-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide in three tumor-derived cell lines (A375, D54, SET-2), which correlated with inhibition of downstream AKT and ERK1/2 phosphorylation. Compounds N-(2-(2-(2-(2-((4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6-morpholino-1,3,5-triazin-2-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide and N-((3-(4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6morpholino-1,3,5-triazin-2-yl)-1-hydroxy-6,9,12-trioxa-3azatetradecan-14-yl)oxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide also demonstrated in vivo tolerability with therapeutic efficacy through reduction of kinase activation and amelioration of disease phenotypes in the JAK2V617F mutant myelofibrosis mouse cancer model. Taken together, these results support further structure optimization of N-(2-(2-(2-(2-((4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6-morpholino-1,3,5-triazin-2-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide and N-((3-(4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6morpholino-1,3,5-triazin-2-yl)-1-hydroxy-6,9,12-trioxa-3azatetradecan-14-yl)oxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide as promising leads for combination therapy in human cancer as a new class of PI3K/MEK bifunctional inhibitors. This study involved multiple reactions and reactants, such as 2-Methoxyethylamine (cas: 109-85-3Computed Properties of C3H9NO).
2-Methoxyethylamine (cas: 109-85-3) belongs to ethers. Esters typically have a pleasant smell; those of low molecular weight are commonly used as fragrances and are found in essential oils and pheromones. Cyclic esters are called lactones, regardless of whether they are derived from an organic or inorganic acid. One example of an organic lactone is γ-valerolactone.Computed Properties of C3H9NO
Referemce:
Ether – Wikipedia,
Ether | (C2H5)2O – PubChem