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Proviral integration site for moloney murine leukemia virus (PIM) kinases are highly expressed in hematological cancers. They phosphorylate downstream substrates that contribute to tumor growth and survival. Therefore, a potent inhibitor of PIM kinases is expected to be effective at treating hematological cancers. In the present study, several indole derivatives of 1,3,4‐oxadiazole‐2(3H)‐thione were synthesized and evaluated as PIM kinase inhibitors. Structure–activity relationship studies yielded potent inhibitors of all three PIM kinases in the single‐digit to low double‐digit nanomolar IC50 range. Kinase profiling of a representative compound showed high selectivity among 15 other kinases. [ABSTRACT FROM AUTHOR]

The proviral integration site for moloney murine leukemia virus (Pim) kinases, consisting of Pim-1, Pim-2 and Pim-3, belongs to a family of serine/threonine kinases that are involved in controlling cell growth and differentiation. Pim kinases are emerging as important mediators of adipocyte differentiation. SGI-1776, an inhibitor of Pim kinases, is widely used to assess the physiological roles of Pim kinases, particularly cell functions. In the present study, we examined the effects of SGI-1776 on adipogenesis. The anti‑adipogenic effect of SGI‑1776 was measured by Oil Red O staining and AdipoRed assays. The effect of SGI‑1776 on the growth of 3T3‑L1 adipocytes was determined by cell count analysis. The effects of SGI‑1776 on the protein and mRNA expression of adipogenesis-related proteins and adipokines in 3T3‑L1 adipocytes were also evaluated by western blot analysis and RT‑PCR, respectively. Notably, SGI-1776 markedly inhibited lipid accumulation during the differentiation of 3T3-L1 preadipocytes into adipocytes. On a mechanistic level, SGI-1776 inhibited not only the expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ) and fatty acid synthase (FAS), but also the phosphorylation of signal transducer and activator of transcription-3 (STAT-3). Moreover, SGI-1776 decreased the expression of adipokines, including the expression of leptin and regulated on activation, normal T cell expressed and secreted (RANTES) during adipocyte differentiation. These findings demonstrate that SGI-1776 inhibits adipogenesis by downregulating the expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS and STAT-3.

The phosphoinositide 3-kinase-Akt signaling pathway is essential to many biological processes, including cell proliferation, survival, metabolism, and angiogenesis, under pathophysiological conditions. Although 3-phosphoinositide-dependent kinase 1 (PDK1) is a primary activator of Akt at the plasma membrane, the optimal activation mechanism remains unclear. We report that adhesion molecule with IgG-like domain 2 (AMIGO2) is a novel scaffold protein that regulates PDK1 membrane localization and Akt activation. Loss of AMIGO2 in endothelial cells (ECs) led to apoptosis and inhibition of angiogenesis with Akt inactivation. Amino acid residues 465-474 in AMIGO2 directly bind to the PDK1 pleckstrin homology domain. A synthetic peptide containing the AMIGO2 465-474 residues abrogated the AMIGO2-PDK1 interaction and Akt activation. Moreover, it effectively suppressed pathological angiogenesis in murine tumor and oxygen-induced retinopathy models. These results demonstrate that AMIGO2 is an important regulator of the PDK1-Akt pathway in ECs and suggest that interference of the PDK1-AMIGO2 interaction might be a novel pharmaceutical target for designing an Akt pathway inhibitor., (© 2015 Park et al.)

Background: Head and neck squamous cell carcinoma (HNSCC) is the 11th leading cancer by incidence worldwide. Surgery and radiotherapy have been the major treatment for patients with HNSCC while chemotherapy has become an important treatment option for locally advanced HNSCC. Understanding of the molecular mechanisms underlying HNSCC impelled the development of targeted therapeutic agents. The development and combinations of targeted therapies in different cellular pathways may be needed to fulfill the unmet needs of current HNSCC chemotherapy., Results: A series of N3-acyl-N5-aryl-3,5-diaminoindazoles were synthesized and their anti-proliferative activities were evaluated against human cancer cell lines, Caki, A549, AMC-HN1, AMC-HN3, AMC-HN4, AMC-HN6, and SNU449. The cellular selectivity of compound was obtained by the modification of substituent at N5-aryl group of 3,5-diaminoindazole. Compound 9a and 9b showed more than 7-fold selectivity for AMC-HN4 and AMC-HN3, respectively., Conclusions: N3-acyl-N5-aryl-3,5-diaminoindazole analogues can be used as hits in the development of anticancer drug for HNSCC.