title: Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window.
abstract: p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window. To attempt mitigating the toxicity, we introduced significant structural changes, culminating in the discovery of the potent pyridone side chain analogue G-9791. Mouse tolerability studies with this compound, other members of this series, and compounds from two structurally distinct classes revealed persistent toxicity and a correlation of minimum toxic concentrations and PAK1/2 mediated cellular potencies. Broad screening of selected PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets. Our data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition, and cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery.
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Murray
authors.forename: Chudi O
authors.initials: CO
authors.lastname: Ndubaku
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aliagas
authors.forename: Lewis
authors.initials: L
authors.lastname: Gazzard
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.forename: Joy
authors.initials: J
authors.lastname: Drobnick
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.forename: Xianrui
authors.initials: X
authors.lastname: Zhao
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.affiliation: Shanghai Chempartner Inc. , 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, People's Republic of China.
authors.forename: David A
authors.initials: DA
authors.lastname: Favor
authors.affiliation: Shanghai Chempartner Inc. , 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Dong
authors.forename: Haiming
authors.initials: H
authors.lastname: Zhang
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Heise
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.forename: Christy C
authors.initials: CC
authors.lastname: Ong
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.forename: Paroma
authors.initials: P
authors.lastname: Chakravarty
authors.forename: Connie
authors.initials: C
authors.lastname: Chan
authors.forename: Diana
authors.initials: D
authors.lastname: Jakubiak
authors.forename: Jennifer
authors.initials: J
authors.lastname: Epler
authors.forename: Sreemathy
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Roxanne
authors.initials: R
authors.lastname: Vega
authors.forename: Gary
authors.initials: G
authors.lastname: Cain
authors.forename: Dolores
authors.initials: D
authors.lastname: Diaz
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhong
mesh_terms: D000208:Acute Disease; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000619636:G-5555 compound; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011728:Pyridones; D011743:Pyrimidines; C515905:Pak1 protein, mouse; C515909:Pak2 protein, mouse; D054462:p21-Activated Kinases