title: Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety.
abstract: Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pK a and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Chudi O
authors.initials: CO
authors.lastname: Ndubaku
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Joy
authors.initials: J
authors.lastname: Drobnick
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aliagas
authors.affiliation: Afraxis, Inc. , 6605 Nancy Ridge Road, Suite 224, San Diego, California 92121, United States.
authors.forename: David
authors.initials: D
authors.lastname: Campbell
authors.affiliation: Shanghai ChemPartner , 576 Libing Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, PRC.
authors.forename: Ping
authors.initials: P
authors.lastname: Dong
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Dornan
authors.affiliation: Afraxis, Inc. , 6605 Nancy Ridge Road, Suite 224, San Diego, California 92121, United States.
authors.forename: Sergio
authors.initials: S
authors.lastname: Duron
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Epler
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lewis
authors.initials: L
authors.lastname: Gazzard
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Heise
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Diana
authors.initials: D
authors.lastname: Jakubiak
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Baiwei
authors.initials: B
authors.lastname: Lin
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
authors.affiliation: Perelman School of Medicine, University of Pennsylvania , 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Jasna
authors.initials: J
authors.lastname: Maksimoska
authors.affiliation: Perelman School of Medicine, University of Pennsylvania , 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Murray
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Sreemathy
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Xianrui
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
keywords: Kinase inhibitor; hERG; oncology; pKa