Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors.
A fragment-based lead discovery approach was used to discover novel ERK2 inhibitors. The crystal structure of N-benzyl-9H-purin-6-amine 1 in complex with ERK2 elucidated its hinge-binding mode. In addition, the simultaneous binding of an imidazole molecule adjacent to 1 suggested a direction for fragment expansion. Structure-based core hopping applied to 1 led to 5H-pyrrolo[3,2-b]pyrazine (3) that afforded direct vectors to probe the pockets of interest while retaining the essential hinge binding elements. Utilizing the new vectors for SAR exploration, the new core 3 was quickly optimized to compound 39 resulting in a greater than 6600-fold improvement in potency.
Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, United States. Electronic address: burdick.dan@gene.com.
Daniel J
DJ
Burdick
Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, United States.
Shumei
S
Wang
Department of Biochemical Pharmacology, Genentech, Inc., South San Francisco, CA 94080, United States.
Christopher
C
Heise
Department of Structural Biology, Genentech, Inc., South San Francisco, CA 94080, United States.
Borlan
B
Pan
Department of Biochemical Pharmacology, Genentech, Inc., South San Francisco, CA 94080, United States.
Jake
J
Drummond
Department of Structural Biology, Genentech, Inc., South San Francisco, CA 94080, United States.
JianPing
J
Yin
Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, United States.
Lauren
L
Goeser
Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, United States.
Steven
S
Magnuson
Department of Computational Chemistry, Genentech, Inc., South San Francisco, CA 94080, United States.
Jeff
J
Blaney
Department of Biochemical Pharmacology, Genentech, Inc., South San Francisco, CA 94080, United States.
John
J
Moffat
Department of Structural Biology, Genentech, Inc., South San Francisco, CA 94080, United States. Electronic address: wang.weiru@gene.com.
Weiru
W
Wang
Department of Computational Chemistry, Genentech, Inc., South San Francisco, CA 94080, United States. Electronic address: chen.huifen@gene.com.
Huifen
H
Chen
D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011719:Pyrazines; D011758:Pyrroles; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1
ERK2; Extracellular-regulated kinase; Fragment-based; Pyrrolopyrazine