No abstract

Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common genetic lesions in acute myeloid leukemia patients (AML). Although FLT3 tyrosine kinase inhibitors initially exhibit clinical activity, resistance to treatment inevitably occurs within months. PIM kinases are thought to be major drivers of the resistance phenotype and their inhibition in relapsed samples restores cell sensitivity to FLT3 inhibitors. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy. For such reasons, we have developed SEL24-B489 - a potent, dual PIM and FLT3-ITD inhibitor. SEL24-B489 exhibited significantly broader on-target activity in AML cell lines and primary AML blasts than selective FLT3-ITD or PIM inhibitors. SEL24-B489 also demonstrated marked activity in cells bearing FLT3 tyrosine kinase domain (TKD) mutations that lead to FLT3 inhibitor resistance. Moreover, SEL24-B489 inhibited the growth of a broad panel of AML cell lines in xenograft models with a clear pharmacodynamic-pharmacokinetic relationship. Taken together, our data highlight the unique dual activity of the SEL24-B489 that abrogates the activity of signaling circuits involved in proliferation, inhibition of apoptosis and protein translation/metabolism. These results underscore the therapeutic potential of the dual PIM/FLT3-ITD inhibitor for the treatment of AML.

Pyrazine derivativesPyrazine derivatives R 0550 Investigations on the Synthesis and Pharmacological Properties of 4-Alkoxy-2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl]-6-methyl-1H-pyrrolo[3,4-c]pyri-dine-1,3(2H)-diones. -All the title compounds (III) exhibit potent analgesic activity which is superior to that of acetylsalicylic acid in two different tests. Furthermore, most of the imides suppress significantly spontaneous locomotor activity in mice. -(SLADOWSKA*, H.; FILIPEK, B.; SZKATULA, D.; SABINIARZ, A.; KARDASZ, M.; POTOCZEK, J.; SIEKLUCKA-DZIUBA, M.; RAJTAR, G.; KLEINROK, Z.; LIS, T.; Farmaco 57 (2002) 11, 897-908; Dep. Chem. Drugs, Wroclaw Univ. Med., PL-50-137 Wroclaw, Pol.; Eng.) -M. Kowall 10-162

No abstract

Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK‐2 plays a significant role by producing fructose‐2,6‐biphosphate; the most potent activator of the glycolysis rate‐limiting step performed by phosphofructokinase PFK‐1. Herein, the synthesis, biological evaluation and structure–activity relationship of novel inhibitors of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3), which is the ubiquitous and hypoxia‐induced isoform of PFK‐2, are reported. X‐ray crystallography and docking were instrumental in the design and optimisation of a series of N‐aryl 6‐aminoquinoxalines. The most potent representative, N‐(4‐methanesulfonylpyridin‐3‐yl)‐8‐(3‐methyl‐1‐benzothiophen‐5‐yl)quinoxalin‐6‐amine, displayed an IC50 of 14 nm for the target and an IC50 of 0.49 μm for fructose‐2,6‐biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology.