title: Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor.
abstract: The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase.
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Alexei S
authors.initials: AS
authors.lastname: Karpov
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Payman
authors.initials: P
authors.lastname: Amiri
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Bellamacina
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Bellance
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Werner
authors.initials: W
authors.lastname: Breitenstein
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Dylan
authors.initials: D
authors.lastname: Daniel
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Regis
authors.initials: R
authors.lastname: Denay
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Cesar
authors.initials: C
authors.lastname: Fernandez
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Inga
authors.initials: I
authors.lastname: Galuba
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Guerro-Lagasse
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Sascha
authors.initials: S
authors.lastname: Gutmann
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Hinh
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jahnke
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Klopp
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Mika K
authors.initials: MK
authors.lastname: Lindvall
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Ma
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Henrik
authors.initials: H
authors.lastname: Möbitz
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Sabina
authors.initials: S
authors.lastname: Pecchi
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rummel
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shoemaker
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Trappe
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Voliva
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.affiliation: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Marzinzik
keywords: PAK1; allosteric inhibitor; dibenzodiazepine; p21 activated kinase; tool compound