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Synthesis and SAR study of modulators inhibiting tRXR?-dependent AKT activation.

ABSTRACT: RXR? represents an intriguing and unique target for pharmacologic interventions. We recently showed that Sulindac and a designed analog could bind to RXR? and modulate its biological activity, including inhibition of the interaction of an N-terminally truncated RXR? (tRXR?) with the p85? regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K). Here we report the synthesis, testing and SAR of a series of novel analogs of Sulindac as potential modulators for inhibiting tRXR?-dependent AKT activation. A new compound 30 was identified to have improved biological activity.

SUBMITTER: Wang ZG

PROVIDER: S-EPMC3738195 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Synthesis and SAR study of modulators inhibiting tRXRα-dependent AKT activation.

Wang Zhi-Gang ZG Chen Liqun L Chen Jiebo J Zheng Jian-Feng JF Gao Weiwei W Zeng Zhiping Z Zhou Hu H Zhang Xiao-Kun XK Huang Pei-Qiang PQ Su Ying Y

European journal of medicinal chemistry 20130118

RXRα represents an intriguing and unique target for pharmacologic interventions. We recently showed that Sulindac and a designed analog could bind to RXRα and modulate its biological activity, including inhibition of the interaction of an N-terminally truncated RXRα (tRXRα) with the p85α regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K). Here we report the synthesis, testing and SAR of a series of novel analogs of Sulindac as potential modulators for inhibiting tRXRα-dependent AKT ac ...[more]

PMID: 23434637

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Project description:Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-?B/p65 nuclear localization and repression of NF-?B targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-?B, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-?B inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis.

Dataset Information

Synthesis and SAR study of modulators inhibiting tRXR?-dependent AKT activation.

Publications

Synthesis and SAR study of modulators inhibiting tRXRα-dependent AKT activation.

Similar Datasets

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