Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection

Burchat, Andrew; Borhani, David W.; Calderwood, David J.; Hirst, Gavin C.; Li, Biqin; Stachlewitz, Robert F.

doi:10.1016/j.bmcl.2005.09.039

Cited by 72 publications

(33 citation statements)

References 5 publications

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“…These 8 small molecule compounds include inhibitors targeting multiple pan-tyrosine kinases such as Src family kinase (A-770041), kinases in cell cycle regulations such as PLK1 (GSK461364), CDK (GP74514A), and kinases in cell stress responses such as JNK (JNK-IN-X). Further studies validated A-770041, a compound previously reported as a highly potent pan-Src family kinase inhibitor [31–33], as the top one of the most effective MDR reversing agents when used in combination with doxorubicin or paclitaxel, as determined by drug sensitivity assays. Because of their target specificity and wide range coverage of the human kinome, the kinase inhibitor focused library compounds were anticipated to be useful to more easily identify the kinase mediators of cancer cell survival associated signaling that could be exploited for the purpose of drug development.…”

Section: Resultsmentioning

confidence: 89%

“…A-770041 was reported as an inhibitor Lck, a Src-family kinase expressed in lymphocytes [31, 32]. We examined the effect of A-770041 on increasing the chemotherapy sensitivities of osteosarcoma MDR cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…Small molecular compounds capable of inhibiting specific kinases and Pgp represent a desirable approach for overcoming Pgp-mediated drug resistance in human cancer. In this study, we report that A-770041, a known Src family kinase inhibitor originally developed as an immunosuppressant to prevent acute graft rejection [31–33], is a novel MDR reversing agent whose mechanism of action includes both the inhibition of Src and Lck activation and expression, and the inhibition of Pgp function by increases the intracellular drug accumulation.…”

Section: Discussionmentioning

confidence: 99%

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A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells

Duan

Zhang

et al. 2014

BMC Cancer

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BackgroundReversing multidrug resistance (MDR) has been an important goal for clinical and investigational oncologists. In the last few decades, significant effort has been made to search for inhibitors to reverse MDR by targeting ATP-binding cassette (ABC) transporters (Pgp, MRP) directly, but these efforts have achieved little clinical success. Protein kinases play important roles in many aspects of tumor cell growth and survival. Combinations of kinase inhibitors and chemotherapeutics have been observed to overcome cancer drug resistance in certain circumstances.MethodsWe screened a kinase specific inhibitor compound library in human osteosarcoma MDR cell lines to identify inhibitors that were capable of reversing chemoresistance to doxorubicin and paclitaxel.ResultsWe identified 18 small molecules that significantly increase chemotherapy drug-induced cell death in human osteosarcoma MDR cell lines U-2OSMR and KHOSR2. We identified A-770041 as one of the most effective MDR reversing agents when combined with doxorubicin or paclitaxel. A-770041 is a potent Src family kinase (Lck and Src) inhibitor. Western blot analysis revealed A-770041 inhibits both Src and Lck activation and expression. Inhibition of Src expression in U-2OSMR and KHOSR2 cell lines using lentiviral shRNA also resulted in increased doxorubicin and paclitaxel drug sensitivity. A-770041 increases the intracellular drug accumulation as demonstrated by calcein AM assay.ConclusionsThese results indicate that small molecule inhibitor A-770041 may function to reverse ABCB1/Pgp-mediated chemotherapy drug resistance. Combination of Src family kinase inhibitor with regular chemotherapy drug could be clinically effective in MDR osteosarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-681) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells

Duan

Zhang

et al. 2014

BMC Cancer

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“…This may be the most relevant finding in our results because it opens the opportunity to titrate concentrations of each individual drug below toxicity levels while maintaining the ability to quell aberrant T-cell activation. Further studies combining Lck inhibitors, such as dasatinib or the recently described A-770041, 43,44 with costimulatory blockade may also provide new routes to achieve desired levels of immunomodulation while minimizing side effects. Therefore, new dosing schedules could be developed to optimize SFK inhibition in the context of concurrent NFAT, mTOR, or JAK inhibition.…”

Section: Discussionmentioning

confidence: 99%

Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation

Schade

Schieven

Townsend

et al. 2008

Blood

253

229

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“…Numerous studies have suggested that T-cells play an important role in corneal graft rejection,53–55 and the Lck inhibitors have proved to be able to prevent solid organ transplant rejection, including kidney and heart transplantation 56–58. This evidence indicated that nintedanib, with the ability of inhibiting Lck, might have an effect to prevent corneal graft rejection by immune suppression.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib

Lin¹,

Gong²

2017

DDDT

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PurposeTo investigate the feasibility of nintedanib, a novel triple angiokinase inhibitor, for inhibiting lymphatic endothelial cell (LEC)-induced lymphangiogenesis in vitro and inflammatory corneal lymphangiogenesis in vivo.Materials and methodsMethylthiazolyldiphenyl-tetrazolium bromide (MTT) test, transwell system, and tube-formation assay were used to evaluate the effects of nintedanib on the proliferation, migration, and tube formation of LECs stimulated by vascular endothelial growth factor-C (VEGF-C), basic fibroblast growth factor (bFGF), or platelet-derived growth factor-BB (PDGF-BB). The murine model of suture-induced corneal neovascularization was used to assess the anti-hemangiogenic and anti-lymphangiogenic effects of nintedanib via systemic and topical applications. Corneal flatmounts were stained with lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and CD31, and the areas of involved blood and lymph vessels were analyzed morphometrically. Corneal cryosections were stained with F4/80 to evaluate inflammatory cell recruitment.ResultsWe observed a significant enhanced effect of LEC proliferation, migration, and tube formation with the administration of VEGF-C, PDGF-BB, and bFGF, respectively, which was diminished by nintedanib. Both topical and systemic applications of nintedanib inhibited suture-induced hemangiogenesis and lymphangiogenesis in the murine cornea. A reduction in F4/80+ cell infiltration was observed at day 14 after corneal suture for both systemic and topical applications of nintedanib. In comparison with controls, 61% of F4/80+ cell recruitment was inhibited via the systemic application of nintedanib, while 49% of F4/80+ cell recruitment was inhibited with the topical application of nintedanib.ConclusionNintedanib was shown to inhibit in vitro lymphangiogenesis stimulated by VEGF-C, bFGF, and PDGF-BB. Applied topically or systemically, it effectively inhibited corneal hemangiogenesis and lymphangiogenesis, accompanied by reduced inflammatory cell recruitment, which represents a new promising treatment for graft rejection after penetrating keratoplasty.

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Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection

Cited by 72 publications

References 5 publications

A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells

A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells

Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation

Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib

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