Assay format as a critical success factor for identification of novel inhibitor chemotypes of tissue-nonspecific alkaline phosphatase from high-throughput screening.

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Thomas ChungJose Luis Millán

Abstract

The tissue-nonspecific alkaline phosphatase (TNAP) isozyme is centrally involved in the control of normal skeletal mineralization and pathophysiological abnormalities that lead to disease states such as hypophosphatasia, osteoarthritis, ankylosis and vascular calcification. TNAP acts in concert with the nucleoside triphosphate pyrophosphohydrolase-1 (NPP1) and the Ankylosis protein to regulate the extracellular concentrations of inorganic pyrophosphate (PP(i)), a potent inhibitor of mineralization. In this review we describe the serial development of two miniaturized high-throughput screens (HTS) for TNAP inhibitors that differ in both signal generation and detection formats, but more critically in the concentrations of a terminal alcohol acceptor used. These assay improvements allowed the rescue of the initially unsuccessful screening campaign against a large small molecule chemical library, but moreover enabled the discovery of several unique classes of molecules with distinct mechanisms of action and selectivity against the related placental (PLAP) and intestinal (IAP) alkaline phosphatase isozymes. This illustrates the underappreciated impact of the underlying fundamental assay configuration on screening success, beyond mer...Continue Reading

References

Oct 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·P S HenthornM P Whyte
May 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·J L Millán, T Manes
Nov 1, 1969·Archives of Internal Medicine·R G RussellH Fleisch
May 15, 1984·Archives of Biochemistry and Biophysics·J L Meyer
Jan 1, 1994·The Journal of Clinical Investigation·A MahmoodD H Alpers
Mar 1, 1997·Developmental Dynamics : an Official Publication of the American Association of Anatomists·S NarisawaJ L Millán
Mar 20, 1999·The Journal of Biological Chemistry·K M HoltzE R Kantrowitz
May 20, 1999·Human Molecular Genetics·L ZurutuzaE Mornet
Jun 11, 1999·Analytical Biochemistry·E B CoganO H Griffith
Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
Jan 9, 2001·Dermatology : International Journal for Clinical and Investigative Dermatology·A KawadaH Orimo
Apr 9, 2002·The Journal of Biological Chemistry·Alexey KozlenkovJosé Luis Millán
May 28, 2002·Methods in Molecular Biology·Jinzi J Wu
Jun 26, 2002·Proceedings of the National Academy of Sciences of the United States of America·Lovisa HessleJosé Luis Millan
Dec 6, 2002·American Journal of Physiology. Gastrointestinal and Liver Physiology·Andromeda M NauliPatrick Tso
Mar 28, 2003·American Journal of Physiology. Gastrointestinal and Liver Physiology·Akhtar MahmoodDavid H Alpers
Jul 26, 2003·Nature Genetics·Frank RutschPeter Nürnberg
Oct 16, 2003·Molecular and Cellular Biology·Sonoko NarisawaJosé Luis Millán
Oct 13, 2004·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Alexey KozlenkovJosé Luis Millán
Apr 13, 2005·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Masae Goseki-SoneTakayuki Hosoi
Jun 17, 2005·Journal of the American Society of Nephrology : JASN·Koba A LomashviliW Charles O'Neill
Jan 18, 2006·Biochemical and Biophysical Research Communications·Takanari NakanoTsugikazu Komoda
Aug 31, 2006·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Dympna HarmeyJosé Luis Millán
Oct 3, 2006·BioFactors·Okezie I AruomaTheeshan Bahorun
Mar 3, 2007·American Journal of Physiology. Gastrointestinal and Liver Physiology·Takanari NakanoTsugikazu Komoda
Jul 20, 2007·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Sonoko NarisawaJose Luis Millán
Sep 29, 2007·American Journal of Physiology. Gastrointestinal and Liver Physiology·Sonoko NarisawaJosé Luis Millán
Dec 19, 2007·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·José Luis MillánMichael P Whyte
Feb 23, 2008·Proceedings of the National Academy of Sciences of the United States of America·Ross F GoldbergRichard A Hodin
Aug 6, 2008·Journal of Medicinal Chemistry·Harshani R LawrenceNicholas J Lawrence
Nov 29, 2008·Bioorganic & Medicinal Chemistry Letters·Shyama SidiqueNicholas D P Cosford
Oct 31, 2009·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Pietro CiancagliniJosé Luis Millán
Dec 25, 2009·Bioorganic & Medicinal Chemistry·Marion LanierJohn R Cashman

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Citations

Aug 14, 2012·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Tina Kiffer-MoreiraJosé Luis Millán
Aug 16, 2014·Bioorganic & Medicinal Chemistry Letters·Yalda BravoNicholas D P Cosford
Dec 3, 2014·Biochemical Pharmacology·Sang-Yong LeeChrista E Müller
Feb 16, 2018·Calcified Tissue International·Jordi BoverMario Cozzolino
Feb 3, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Jamshed IqbalChang-Hyun Oh
Mar 28, 2013·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Siming WangYi Yang
Nov 9, 2020·Biochemical Pharmacology·Herbert Zimmermann

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Methods Mentioned

BETA
transgenic
PLAP
Assay
scintillation proximity

Software Mentioned

Chemistry Component Pipeline Pilot

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