Medicinal chemistry approaches to target the MNK-eIF4E axis in cancer.

Aberrant translation of proteins that promote cell proliferation is an essential factor that defines oncogenic processes and cancer. The process for ribosomal translation of proteins from mRNA requires an essential initiation step which is controlled by the protein eIF4E, which binds the RNA 5'-cap and forms the eIF4F complex that subsequently translates protein. Typically, eIF4E is activated by phosphorylation on Ser209 by MNK1 and MNK2 kinases. Substantial work has shown that eIF4E and MNK1/2 are dysregulated in many cancers and this axis has therefore become an active area of interest for developing new cancer therapeutics. This review summarizes and discusses recent work to develop small molecules that target different steps in the MNK-eIF4E axis as potential cancer therapeutics. The aim of this review is to cover the breadth of different molecular approaches being taken and the medicinal chemistry basis for their optimization and testing as new cancer therapeutics.

Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.

Chemoenzymatic route to stereodefined 2-(azidophenyl)oxazolines for click chemistry.

Aryl-substituted esters of a racemic diprotected 2-azido-1-alkanol were submitted to the Staudinger/aza-Wittig reaction in order to assess scope and establish conditions for their cyclization to the corresponding 2,4,5-trisubstituted oxazolines. Following the cyclization study, the (2R,3R)-antipode of the azidoalkanol was obtained in high ee by incubation of the corresponding racemic azidoacetate with pig liver esterase (PLE). The p-nitrobenzoate of the enantioenriched 2-azido-1-alcohol was cyclized by the Staudinger/aza-Wittig to give the corresponding (4R,5R)-disubstituted-2-(4-nitrophenyl) oxazoline. Selective reduction of the nitrophenyloxazoline to the corresponding aminophenyloxazoline using aluminum amalgam followed by direct azidation of the 2-(4-aminophenyl) moiety provided the corresponding (4R,5R)-2-(4-azidophenyl) oxazoline derivative. The azidophenyl oxazoline was reacted with a proven click partner 4-ethynylfluorobenzene under copper/sodium ascorbate mediation to provide the click triazole product in high yield.

Applicability of aluminum amalgam to the reduction of arylnitro groups.

An array of arylnitro compounds with various functionality were treated with freshly-prepared aluminum amalgam in THF/water solution and resulted in the corresponding arylamines. The Al(Hg)-mediated reductions are relatively rapid with consumption of the amalgam and disappearance of starting material occurring over 20-30 minutes. The workup of the reductions involves only removal of the insoluble by-products by filtration followed by concentration. Only in some cases is chromatography required to secure the pure product. The desired arylamines are furnished in quantities of 25-100 mg, which in some cases, could be taken on to the next reaction without further purification. Reductions of 4-nitrobenzyl derivatives of carbohydrates or nucleosides were selective in affording the corresponding 4-aminobenzyl products. To show applicability in click chemistry, selected aminobenzyl products are directly azidated to yield products that were then used in click reactions to afford the corresponding 1,2,3-triazoles.

Antiangiogenic Activity and Chemical Derivatization of the Neurotoxic Acetogenin Annonacin Isolated from Asimina triloba.

Annonacin (1) was isolated from the North American pawpaw ( Asimina triloba), as reported earlier from these laboratories. Natural 1 was submitted to the rat aortic ring bioassay for evaluation of antiangiogenic activity and was found to inhibit microvessel growth (IC50 value of 3 µM). 4,10,15,20-Tetraazido derivatives of 1 were prepared by permesylation followed by azide displacement or by iodination followed by azide displacement. The tetraazide derived from mesylation/azidation was antiangiogenic, while that derived from iodination/azidation exhibited no appreciable activity. The membrane permeability of natural 1 was evaluated using the parallel artificial membrane permeability assay and was found to be marginally permeable as compared to several clinically relevant compounds.