title: Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors.
abstract: MAP4K4 has been shown to regulate key cellular processes that are tied to disease pathogenesis. In an effort to generate small molecule MAP4K4 inhibitors, a fragment-based screen was carried out and a pyrrolotriazine fragment with excellent ligand efficiency was identified. Further modification of this fragment guided by X-ray crystal structures and molecular modeling led to the discovery of a series of promising compounds with good structural diversity and physicochemical properties. These compounds exhibited single digit nanomolar potency and compounds 35 and 44 achieved good in vivo exposure.
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Stanley
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Boggs
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Crawford
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Bravo
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Giannetti
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Magnuson
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Weilan
authors.initials: W
authors.lastname: Ye
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Murray
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: ndubaku.chudi@gene.com.
authors.forename: Chudi O
authors.initials: CO
authors.lastname: Ndubaku
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: chen.huifen@gene.com.
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D014227:Triazines; D000097782:NF-kappaB-Inducing Kinase; C000596678:pyrrolo(2,1-f)(1,2,4)triazine; C117090:MAP4K4 protein, human
keywords: Fragment-based lead discovery; Kinase inhibitors; MAP4K4; P-loop conformation; Pyrrolotriazine