OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance

Biochemical Pharmacology
Ye-Hong KuangZhe-Sheng Chen

Abstract

OSI-930, a dual c-Kit and KDR tyrosine kinase inhibitor, is reported to have undergone a Phase I dose escalation study in patients with advanced solid tumors. A series of fifteen pyridyl and phenyl analogues of OSI-930 were designed and synthesized. Extensive screening of these compounds led to the discovery that nitropyridyl and ortho-nitrophenyl analogues, VKJP1 and VKJP3, were effective in reversing ABC subfamily G member 2 (ABCG2) transporter-mediated multidrug resistance (MDR). VKJP1 and VKJP3 significantly sensitized ABCG2-expressing cells to established substrates of ABCG2 including mitoxantrone, SN-38, and doxorubicin in a concentration-dependent manner, but not to the non-ABCG2 substrate cisplatin. However, they were unable to reverse ABCB1- or ABCC1-mediated MDR indicating their selectivity for ABCG2. Western blotting analysis was performed to evaluate ABCG2 expression and it was found that neither VKJP1 nor VKJP3 significantly altered ABCG2 protein expression for up to 72 h. [(3)H]-mitoxantrone accumulation study demonstrated that VKJP1 and VKJP3 increased the intracellular accumulation of [(3)H]-mitoxantrone, a substrate of ABCG2. VKJP1 and VKJP3 also remarkably inhibited the transport of [(3)H]-methotrexate by ABCG...Continue Reading

References

Nov 11, 1976·Biochimica Et Biophysica Acta·R L Juliano, V Ling
Mar 1, 1985·Somatic Cell and Molecular Genetics·S AkiyamaM M Gottesman
Dec 23, 1998·Proceedings of the National Academy of Sciences of the United States of America·L A DoyleD D Ross
Mar 16, 2000·Proceedings of the National Academy of Sciences of the United States of America·Z E Sauna, S V Ambudkar
Sep 7, 2000·Current Opinion in Oncology·B TanL Ratner
Jan 31, 2002·Annual Review of Medicine·Michael M Gottesman
Mar 21, 2002·Nature Reviews. Cancer·Michael M GottesmanSusan E Bates
Oct 9, 2002·Current Protein & Peptide Science·Karin F K Ejendal, Christine A Hrycyna
Jan 22, 2003·Advanced Drug Delivery Reviews·Alfred H Schinkel, Johan W Jonker
Jan 22, 2003·Advanced Drug Delivery Reviews·Anne H DantzigMichael Burgess
Oct 25, 2003·Oncogene·Gary D Kruh, Martin G Belinsky
Oct 31, 2003·Journal of Medicinal Chemistry·Jacques Robert, Christian Jarry
Aug 30, 2005·Annual Review of Genomics and Human Genetics·Michael Dean, Tarmo Annilo
Sep 9, 2005·The AAPS Journal·Qingcheng Mao, Jashvant D Unadkat
Apr 18, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Weiguo LiuAllan R Oseroff
Dec 9, 2008·Biochemical Pharmacology·Zhi ShiZhe-Sheng Chen
Jan 30, 2010·Chinese Journal of Cancer·Yuan Zhou, Xian-Long Ling
Jul 21, 2011·Molecular Pharmaceutics·Chung-Pu WuYu-Shan Wu
Sep 17, 2011·Bioorganic & Medicinal Chemistry Letters·Jay P PatelVijaya L Korlipara

❮ Previous
Next ❯

Citations

Apr 30, 2013·Journal of Dermatological Science·Shuang ZhaoXiang Chen
Jun 11, 2015·American Journal of Hematology·Daniela DamianiRenato Fanin
Dec 12, 2012·European Journal of Clinical Investigation·Wen-Jing WuRui-Hua Xu
Dec 23, 2016·Medicinal Research Reviews·Diana Peña-SolórzanoCristian Ochoa-Puentes
Jul 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Buthina A Al-OudatAmit K Tiwari
Dec 31, 2018·European Journal of Medicinal Chemistry·Katja SilbermannMichael Wiese

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.