title: Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing.
abstract: Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.
authors: Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors: John C
authors: JC
authors: Reader
authors: Thomas P
authors: TP
authors: Matthews
authors: Suki
authors: S
authors: Klair
authors: Kwai-Ming J
authors: KM
authors: Cheung
authors: Jane
authors: J
authors: Scanlon
authors: Nicolas
authors: N
authors: Proisy
authors: Glynn
authors: G
authors: Addison
authors: John
authors: J
authors: Ellard
authors: Nelly
authors: N
authors: Piton
authors: Suzanne
authors: S
authors: Taylor
authors: Michael
authors: M
authors: Cherry
authors: Martin
authors: M
authors: Fisher
authors: Kathy
authors: K
authors: Boxall
authors: Samantha
authors: S
authors: Burns
authors: Michael I
authors: MI
authors: Walton
authors: Isaac M
authors: IM
authors: Westwood
authors: Angela
authors: A
authors: Hayes
authors: Paul
authors: P
authors: Eve
authors: Melanie
authors: M
authors: Valenti
authors: Alexis
authors: A
authors: de Haven Brandon
authors: Gary
authors: G
authors: Box
authors: Rob L M
authors: RL
authors: van Montfort
authors: David H
authors: DH
authors: Williams
authors: G Wynne
authors: GW
authors: Aherne
authors: Florence I
authors: FI
authors: Raynaud
authors: Suzanne A
authors: SA
authors: Eccles
authors: Michelle D
authors: MD
authors: Garrett
authors: Ian
authors: I
authors: Collins
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse