title: Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point.
abstract: There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Richard A
authors.identifier: 0000-0002-2310-9477
authors.initials: RA
authors.lastname: Ward
authors.affiliation: AstraZeneca , Charter Way, Macclesfield, SK10 2NA, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Bethel
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Calum
authors.initials: C
authors.lastname: Cook
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Emma
authors.initials: E
authors.lastname: Davies
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Judit E
authors.initials: JE
authors.lastname: Debreczeni
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Gary
authors.initials: G
authors.lastname: Fairley
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Lyman
authors.initials: L
authors.lastname: Feron
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Vikki
authors.initials: V
authors.lastname: Flemington
authors.affiliation: AstraZeneca , Charter Way, Macclesfield, SK10 2NA, U.K.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Graham
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Ryan
authors.initials: R
authors.lastname: Greenwood
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Nicola
authors.initials: N
authors.lastname: Griffin
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Hanson
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Philip
authors.initials: P
authors.lastname: Hopcroft
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Tina D
authors.initials: TD
authors.lastname: Howard
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Julian
authors.initials: J
authors.lastname: Hudson
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Michael
authors.initials: M
authors.lastname: James
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Jones
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jones
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Scott
authors.initials: S
authors.lastname: Lamont
authors.affiliation: AstraZeneca , Charter Way, Macclesfield, SK10 2NA, U.K.
authors.forename: Richard
authors.initials: R
authors.lastname: Lewis
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Nicola
authors.initials: N
authors.lastname: Lindsay
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Karen
authors.initials: K
authors.lastname: Roberts
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Iain
authors.initials: I
authors.lastname: Simpson
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Steve
authors.initials: S
authors.lastname: St-Gallay
authors.affiliation: AstraZeneca , Charter Way, Macclesfield, SK10 2NA, U.K.
authors.forename: Steve
authors.initials: S
authors.lastname: Swallow
authors.affiliation: Pharmaron Beijing Co., Ltd. , 6 Taihe Road BDA, Beijing, 100176, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Tang
authors.affiliation: IMED Oncology and Discovery Sciences, AstraZeneca , Darwin Building, and AstraZeneca, Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
authors.forename: Michael
authors.initials: M
authors.lastname: Tonge
authors.affiliation: Pharmaron Beijing Co., Ltd. , 6 Taihe Road BDA, Beijing, 100176, P.R. China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Pharmaron Beijing Co., Ltd. , 6 Taihe Road BDA, Beijing, 100176, P.R. China.
authors.forename: Baochang
authors.initials: B
authors.lastname: Zhai
mesh_terms: D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008745:Methylation; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors