title: Discovery of selective 4-Amino-pyridopyrimidine inhibitors of MAP4K4 using fragment-based lead identification and optimization.
abstract: Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like lead compounds. The optimization efforts eventually led us to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. This compound had low nanomolar potency, excellent kinase selectivity, and good in vivo exposure, and demonstrated in vivo pharmacodynamic effects in a human tumor xenograft model.
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Crawford
authors.forename: Chudi O
authors.initials: CO
authors.lastname: Ndubaku
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.forename: Jason W
authors.initials: JW
authors.lastname: Boggs
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Bravo
authors.forename: Kelly
authors.initials: K
authors.lastname: Delatorre
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Giannetti
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: Steven R
authors.initials: SR
authors.lastname: Magnuson
authors.forename: Erin
authors.initials: E
authors.lastname: McNamara
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Murray
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Amy
authors.initials: A
authors.lastname: Sambrone
authors.forename: Stephen
authors.initials: S
authors.lastname: Schmidt
authors.forename: Tanya
authors.initials: T
authors.lastname: Smyczek
authors.forename: Mark
authors.initials: M
authors.lastname: Stanley
authors.forename: Philip
authors.initials: P
authors.lastname: Vitorino
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Kristina
authors.initials: K
authors.lastname: West
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Weilan
authors.initials: W
authors.lastname: Ye
mesh_terms: D000818:Animals; D055808:Drug Discovery; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases