title: Fragment-based drug discovery of potent and selective MKK3/6 inhibitors.
abstract: The MAPK signaling cascade, comprised of several linear and intersecting pathways, propagates signaling into the nucleus resulting in cytokine and chemokine release. The Map Kinase Kinase isoforms 3 and 6 (MKK3 and MKK6) are responsible for the phosphorylation and activation of p38, and are hypothesized to play a key role in regulating this pathway without the redundancy seen in downstream effectors. Using FBDD, we have discovered efficient and selective inhibitors of MKK3 and MKK6 that can serve as tool molecules to help further understand the role of these kinases in MAPK signaling, and the potential impact of inhibiting kinases upstream of p38.
authors.affiliation: Medicinal Chemistry, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Adams
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Toshitake
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Computational Sciences and Crystallography, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: J David
authors.initials: JD
authors.lastname: Lawson
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Morihisa
authors.initials: M
authors.lastname: Saitoh
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Shimokawa
authors.affiliation: Medicinal Chemistry, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Simone V
authors.initials: SV
authors.lastname: Bigi
authors.affiliation: Global DMPK, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hixon
authors.affiliation: Medicinal Chemistry, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Smith
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tatamiya
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Goto
authors.affiliation: CNS & Novel Target ID, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Russo
authors.affiliation: Computational Sciences and Crystallography, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Grimshaw
authors.affiliation: Medicinal Chemistry, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Swann
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D048371:MAP Kinase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human
keywords: FBDD; MAP Kinase Kinase 3 (MKK3); MAP Kinase Kinase 6 (MKK6)