Bis(1H-indol-2-yl)methanones are effective inhibitors of FLT3-ITD tyrosine kinase and partially overcome resistance to PKC412A in vitro.

Inhibition of the mutated fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is a promising therapeutic strategy in acute myeloid leukaemia (AML). However, development of resistance to FLT3 tyrosine kinase inhibitors (TKI), such as PKC412A, has been described recently. This observation may have an increasing impact on the duration of response and relapse rates in upcoming clinical trials employing FLT3-TKI. Herein we investigated two representatives of a novel class of FLT3-TKI: Bis(1H-indol-2-yl)methanones. Both compounds effectively induced apoptosis in FLT3-internal tandem duplicate (ITD)-transfected murine myeloid cells and in primary FLT3-ITD positive blasts. Combination of both compounds with chemotherapy revealed synergistic effects in apoptosis assays. The compounds did not show significant toxicity in human bone marrow cells derived from healthy donors. Compound102 overcame resistance to PKC412 within a non-myelotoxic dose-range. Western Blotting experiments of 32D-FLT3-ITD cells showed dose-dependent dephosphorylation of FLT3-ITD and of its downstream targets STAT5, AKT and ERK upon incubation with either compound. In conclusion, bis(1H-indol-2-yl)methanones overcome resistance mediated by FLT3-ITD mutations at position N676 and show strong efficacy in FLT3-ITD-positive cells alone as well as in combination with chemotherapy. We propose that further development of methanone compounds overcoming resistance to currently established FLT3-TKIs is an important step forward to an anticipated need within our future therapeutic algorithm in FLT3-ITD-positive AML.

Consensus anticancer activity profiles derived from the meta-analysis of reference compounds for widely used cell lines.

AIM: To establish a standard reference for bioactivity of widely used anticancer compounds that might be useful for meaningful interpretation of the cell viability data generated for novel synthetic derivatives. MATERIALS & METHODS: Meta-analysis of published IC50 values was carried out for commonly used anticancer compounds and cell viability experiments were performed to validate the role of certain factors in drug activity. RESULTS & CONCLUSION: Variability in the published IC50 values was demonstrated. Based on median IC50 values derived from pooled published data, cell lines were classified as either sensitive or resistant. Further, factors that influence IC50 values were discussed, thus encouraging researchers to devise more rational experimental approaches to enhance the success rate in later stages of drug development.

Synthesis of Novel Imine Stilbene Analogs Exhibiting Potent Anticancer Activity.

BACKGROUND: Resveratrol (RV) and its analogues Aza-stilbenes were found effective in exhibiting anticancer activity. OBJECTIVE: The present study mainly focused on the green synthesis of novel imine stilbene analogues and evaluation of their anticancer activity besides their influence on hypoxia-induced gene expression in cancer cells. METHOD: Novel imine stilbenes, differing in number and/or position of hydroxyl and methoxy functional groups, have been synthesized using green chemistry mediated condensation reaction between aldehydes and amines in the ethanolic extract of Psoralea corylifolia hairy roots and tested for their anticancer potential. RESULTS: Ethanol containing 1% hairy root extract facilitated instant reaction and yielded more than 99% product( s). MTT assay on HeLa cells treated with imine stilbene analogues revealed an increase in the inhibition of cell proliferation as compared to RV. Treatment of nontumor HEK293 cells with these compounds disclosed minimal toxicity implying the selective advantage of these compounds for cervical cancer therapy. Scratch assay on HeLa cells displayed inhibition of directional cell motility by these analogues and compound 3e [4-((E)-(4- hydroxyphenylimino)methyl)-2-methoxyphenol] recorded maximum inhibition. In reporter assay, as compared to untreated N-(2-Methoxy-2-oxoacetyl) glycine methyl ester (DMOG) induced cells, hypoxia response element- directed transcriptional activity has been significantly reduced in DMOG induced cells treated with imine stilbene analogues. CONCLUSION: Overall results indicated that four of the five imine stilbene analogues exhibited enhanced anticancer activity than that of the RV. As such, the novel synthetic compounds 3d, 3e and 3b endowed with potent anticancer activity than RV can serve as drug lead molecules.