title: Structure-based design of potent and selective 2-(quinazolin-2-yl)phenol inhibitors of checkpoint kinase 2.
abstract: Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK. john.caldwell@icr.ac.uk
authors.forename: John J
authors.initials: JJ
authors.lastname: Caldwell
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Welsh
authors.forename: Cornelis
authors.initials: C
authors.lastname: Matijssen
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Anderson
authors.forename: Laurent
authors.initials: L
authors.lastname: Antoni
authors.forename: Kathy
authors.initials: K
authors.lastname: Boxall
authors.forename: Frederique
authors.initials: F
authors.lastname: Urban
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Laurent J M
authors.initials: LJ
authors.lastname: Rigoreau
authors.forename: Tony
authors.initials: T
authors.lastname: Raynham
authors.forename: G Wynne
authors.initials: GW
authors.lastname: Aherne
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: Antony W
authors.initials: AW
authors.lastname: Oliver
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Garrett
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D064447:Checkpoint Kinase 2; D018360:Crystallography, X-Ray; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011837:Radiation-Protective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects
chemical_list: C556313:4-fluoro-2-(4-(4-(2-hydroxypropan-2-yl)pyrrolidin-3-ylamino)-6,7-dimethoxyquinazolin-2-yl)phenol; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010636:Phenols; D011799:Quinazolines; D011837:Radiation-Protective Agents; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases