1735-55-3Relevant articles and documents
Effect of isouronium/guanidinium substitution on the efficacy of a series of novel anti-cancer agents
Previtali, Viola,Trujillo, Cristina,Amet, Rebecca,Zisterer, Daniela M.,Rozas, Isabel
, p. 735 - 743 (2018)
Considering our hypothesis that the guanidinium moiety in the protein kinase type III inhibitor 1 interacts with a phosphate of ATP within the hinge region, the nature of the interactions established between a model isouronium and the phosphate groups of ATP was computationally analysed indicating that an isouronium derivative of 1 will interact in a similar manner with ATP. Thus, a number of compounds were prepared to assess the effect of the guanidinium/isouronium substitution on cancer cell growth; additionally, the molecular shortening and conformational change induced by replacing the di-substituted guanidine-linker of 1 by an amide was explored. The effect of these compounds on cell viability was tested in human leukaemia, breast cancer and cervical cancer cell lines and the resulting IC50 values were compared with those of the lead compound 1. Replacement of the di-substituted guanidine-linker by an amide results in the loss of cytotoxicity; however, substitution of the mono-substituted guanidinium by an isouronium cation seems to be beneficial for cell growth inhibition. Additionally, the effect of these compounds on the MAPK/ERK pathway was studied by means of Western blotting and the results indicate that the isouronium derivative 2 decreases the levels of phosphorylated, and thus activated, ERK (pERK) both in leukaemia and breast cancer cells, whereas lead compound 1 only shows an effect on pERK levels in breast cancer cells. This confirms that both compounds could interfere with the MAPK/ERK pathway although other targets cannot be ruled out.
Discovery of novel phenoxybenzamide analogues as Raf/HDAC dual inhibitors
Geng, Aixin,Cui, Hao,Zhang, Liyuan,Chen, Xin,Li, Hongmei,Lu, Tao,Zhu, Yong
, p. 1605 - 1608 (2019)
Histone deacetylase (HDAC)inhibitors as an important epigenetic therapeutic strategy affect signaling networks and act synergistically with kinase inhibitors for the treatment of cancer. Herein we presented a series of novel phenoxybenzamide analogues with inhibition of Raf and HDAC. Among them, compound 10e showed potent antiproliferative activities against Hepg2 and MDA-MB-468 in cellular assays. This work may lay the foundation for developing novel dual Raf/HDAC inhibitors as potential anticancer therapeutics.
Discovery of potent Pan-Raf inhibitors with increased solubility to overcome drug resistance
Wang, Lu,Zhang, Yanmin,Zhang, Qing,Zhu, Gaoyuan,Zhang, Zhimin,Duan, Chunqi,Lu, Tao,Tang, Weifang
supporting information, p. 243 - 255 (2018/12/11)
Despite various applications of kinase inhibitors in oncology and inflammatory diseases, the emergence of resistance still remains the major barrier to achieve long-term remission in cancer treatment. With the aim of overcoming the resistance induced by type IIB BRaf V600E selective inhibitor vemurafenib, and further ameliorating the antiproliferative activity, a novel type IIA Pan-Raf inhibitors Ia–Io based on pyrrolo[2,3-d] pyrimidine scaffold were designed and evaluated in this work. Herein, we tried to improve the cellular potency of the target compounds by increasing their solubility. Among them, Il, with the solubility of 0.107 mg/mL, demonstrated favorable cellular activity against vemurafenib-resistant carcinoma cells including BRafWT phenotypic melanoma SK-MEL-2 and BRafV600E phenotypic colorectal cancer HT-29 cell lines. Based on the well solubility, Il exhibited good metabolic stability compared to sorafenib and showed favorable pharmacokinetic profiles in rats. As for the biological mechanism research, Il had the similar P-ERK kinase inhibitory activity in A375 and SK-Mel-2 cells as our previously lead P-2. Il may become a good candidate compound to overcome the resistance associated with vemurafenib.
