Kinase inhibition by deoxy analogues of the resorcylic lactone L-783277.

The natural product L-783277 is a resorcylic lactone type covalent kinase inhibitor. We have prepared the 5'-deoxy analogue of L-783277 (1) in a stereoselective fashion. Remarkably, this analogue retains almost the full kinase inhibitory potential of natural L-783277, with low nanomolar IC50 values against the most sensitive kinases, and it exhibits essentially the same selectivity profile (within the panel of 39 kinases investigated). In contrast, removal of both the 4'- and the 5'-hydroxyl groups leads to a more significant reduction in kinase inhibitory activity and so does a change in the geometry of the C7'-C8' double bond in 1 from Z to E. These findings offer new perspectives for the design of second generation resorcylic lactone-based kinase inhibitors.

[1]  Y. Wang,et al.  Discovery of an in vitro and in vivo potent resorcylic lactone analog of LL-Z1640-2 as anti-inflammatory lead, II. , 2010, Bioorganic & medicinal chemistry letters.

[2]  Y. Wang,et al.  Discovery of anti-inflammatory clinical candidate E6201, inspired from resorcylic lactone LL-Z1640-2, III. , 2010, Bioorganic & medicinal chemistry letters.

[3]  S. Barluenga,et al.  Molecular Editing of Kinase‐Targeting Resorcylic Acid Lactones (RAL): Fluoroenone RAL , 2010, ChemMedChem.

[4]  J. Mestan,et al.  Extended kinase profile and properties of the protein kinase inhibitor nilotinib. , 2010, Biochimica et biophysica acta.

[5]  Masaki Goto,et al.  Conformational Analyses and MO Studies of f152A1 and Its Analogues as Potent Protein Kinase Inhibitors , 2009, J. Chem. Inf. Model..

[6]  S. Barluenga,et al.  Divergent syntheses of resorcylic acid lactones: L-783277, LL-Z1640-2, and hypothemycin. , 2009, Chemistry.

[7]  S. Barluenga,et al.  Synthesis of a resorcylic acid lactone (RAL) library using fluorous-mixture synthesis and profile of its selectivity against a panel of kinases. , 2009, Chemistry.

[8]  F. Gusovsky,et al.  E6201 [(3S,4R,5Z,8S,9S,11E)-14-(Ethylamino)-8, 9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione], a Novel Kinase Inhibitor of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase (MEK)-1 and MEK Kinase-1: In Vitro Characterization o , 2009, Journal of Pharmacology and Experimental Therapeutics.

[9]  F. Gusovsky,et al.  Discovery of a potent, metabolically stabilized resorcylic lactone as an anti-inflammatory lead. , 2009, Bioorganic & medicinal chemistry letters.

[10]  Nathanael Gray,et al.  Factors underlying sensitivity of cancers to small-molecule kinase inhibitors , 2009, Nature Reviews Drug Discovery.

[11]  S. Grant.  Therapeutic Protein Kinase Inhibitors , 2009, Cellular and Molecular Life Sciences.

[12]  K. Altmann,et al.  Resorcylic acid lactones as new lead structures for kinase inhibition , 2008 .

[13]  Giulio Rastelli,et al.  Molecular modeling and crystal structure of ERK2-hypothemycin complexes. , 2008, Journal of structural biology.

[14]  K. Altmann,et al.  Total Synthesis of the Resorcylic Lactone-Based Kinase Inhibitor L-783277 , 2008 .

[15]  D. Santi,et al.  Semisynthesis and Cytotoxicity of Hypothemycin Analogues , 2007, ChemMedChem.

[16]  Robert T Abraham,et al.  Targeting the mTOR signaling network in cancer. , 2007, Trends in molecular medicine.

[17]  C. Der,et al.  Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer , 2007, Oncogene.

[18]  S. Barluenga,et al.  Chemistry and Biology of Resorcylic Acid Lactones , 2007 .

[19]  Seiji Yoshimura,et al.  Role of a cysteine residue in the active site of ERK and the MAPKK family. , 2007, Biochemical and biophysical research communications.

[20]  R. Reid,et al.  Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Ninomiya-Tsuji,et al.  A Resorcylic Acid Lactone, 5Z-7-Oxozeaenol, Prevents Inflammation by Inhibiting the Catalytic Activity of TAK1 MAPK Kinase Kinase* , 2003, The Journal of Biological Chemistry.

[22]  Samuel Singer,et al.  PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors , 2003, Science.

[23]  R. Lett.,et al.  Convergent stereospecific synthesis of LL-Z1640-2 (or C292), hypothemycin and related macrolides. Part 2 , 2002 .

[24]  O. Hensens,et al.  Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK. , 1999, The Journal of antibiotics.

[25]  K. Sugita,et al.  Antitumor Efficacy of Hypothemycin, A New Ras‐signaling Inhibitor , 1999, Japanese journal of cancer research : Gann.

[26]  G. E. Keck,et al.  Catalytic asymmetric allylation of aldehydes , 1993 .

[27]  N. Gray,et al.  Targeting cancer with small molecule kinase inhibitors , 2009, Nature Reviews Cancer.