Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket

Journal of Medicinal Chemistry
M YamamotoY Okada

Abstract

The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inh...Continue Reading

References

May 23, 1995·Biochemistry·M F BrownerA L Castelhano
Jun 1, 1994·Proteins·J C SpurlinoT A Pulvino
Jan 1, 1993·Annual Review of Cell Biology·W G Stetler-StevensonL A Liotta
Dec 22, 1995·The Journal of Biological Chemistry·S J AtkinsonG Murphy
Apr 1, 1997·Bioorganic & Medicinal Chemistry·R HirayamaS Ikeda

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Citations

Jul 12, 2003·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·S J LeeI Saiki
Mar 7, 2001·Bioorganic & Medicinal Chemistry Letters·M J Fray, R P Dickinson
Jul 23, 2003·Bioorganic & Medicinal Chemistry Letters·Hideki MoriyamaShin-ichiro Nishimura
Apr 14, 1999·Bioorganic & Medicinal Chemistry Letters·D H Kim, Y Jin
Jun 12, 2002·Bioorganic & Medicinal Chemistry·Tetsunori FujisawaTadanori Morikawa
Apr 9, 2005·European Surgical Research. Europäische Chirurgische Forschung. Recherches Chirurgicales Européennes·U MirastschijskiM S Agren
Feb 5, 1999·Clinical and Experimental Immunology·S Hirohata
Dec 26, 2013·Histochemistry and Cell Biology·Takeomi MizutaniKazushige Kawabata
Jun 29, 2004·Proceedings of the National Academy of Sciences of the United States of America·Alan SaghatelianBenjamin F Cravatt
Aug 10, 2000·Neoplasia : an International Journal for Oncology Research·K MurakamiI Saiki
May 22, 2010·Chemical Biology & Drug Design·Malkeet S Bahia, Om Silakari
Feb 22, 2012·Biochimica Et Biophysica Acta·Janine M WilkinsonIan M Clark
May 2, 2013·The Journal of Allergy and Clinical Immunology·Michelle A HardymanJane E Collins
Jan 16, 2002·The Journal of Biological Chemistry·M Margarida BernardoShahriar Mobashery
Nov 2, 2017·Expert Opinion on Drug Discovery·Yue ZhongJin-Ao Duan
Aug 31, 2002·Developmental Dynamics : an Official Publication of the American Association of Anatomists·D H Cai, P R Brauer
Aug 7, 2004·American Journal of Physiology. Heart and Circulatory Physiology·Peter ZahradkaNatalia Yurkova
Aug 27, 2002·The Journal of Biological Chemistry·Hidayatullah G MunshiM Sharon Stack
Apr 21, 2018·Frontiers in Pharmacology·Péter BencsikPéter Ferdinandy
Oct 16, 2001·American Journal of Physiology. Cell Physiology·C HuetE Engvall
Feb 22, 2001·American Journal of Physiology. Renal Physiology·N ObermüllerR Witzgall
Apr 14, 2018·Scientific Reports·Alexander BraunKenneth A Myers

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