title: Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).
abstract: Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic-pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.
authors.forename: James D
authors.initials: JD
authors.lastname: Osborne
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Matthews
authors.forename: Tatiana
authors.initials: T
authors.lastname: McHardy
authors.forename: Nicolas
authors.initials: N
authors.lastname: Proisy
authors.forename: Kwai-Ming J
authors.initials: KM
authors.lastname: Cheung
authors.forename: Michael
authors.initials: M
authors.lastname: Lainchbury
authors.forename: Nathan
authors.initials: N
authors.lastname: Brown
authors.forename: Michael I
authors.initials: MI
authors.lastname: Walton
authors.forename: Paul D
authors.initials: PD
authors.lastname: Eve
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Boxall
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.forename: Alan T
authors.initials: AT
authors.lastname: Henley
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Valenti
authors.forename: Alexis K
authors.initials: AK
authors.lastname: De Haven Brandon
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.forename: Yann
authors.initials: Y
authors.lastname: Jamin
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Westwood
authors.forename: Rob L M
authors.initials: RL
authors.lastname: van Montfort
authors.affiliation: Sareum Ltd. , Cambridge CB22 3FX, U.K.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Leonard
authors.affiliation: Sareum Ltd. , Cambridge CB22 3FX, U.K.
authors.forename: Marieke B A C
authors.initials: MB
authors.lastname: Lamers
authors.affiliation: Sareum Ltd. , Cambridge CB22 3FX, U.K.
authors.forename: John C
authors.initials: JC
authors.lastname: Reader
authors.forename: G Wynne
authors.initials: GW
authors.lastname: Aherne
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Garrett
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000612152:CCT245737; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D015761:4-Aminopyridine; D000071877:Checkpoint Kinase 1