1. Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing.
- Author
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Reader JC, Matthews TP, Klair S, Cheung KM, Scanlon J, Proisy N, Addison G, Ellard J, Piton N, Taylor S, Cherry M, Fisher M, Boxall K, Burns S, Walton MI, Westwood IM, Hayes A, Eve P, Valenti M, de Haven Brandon A, Box G, van Montfort RL, Williams DH, Aherne GW, Raynaud FI, Eccles SA, Garrett MD, and Collins I
- Subjects
- Adenosine Triphosphate chemistry, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Binding Sites, Biological Availability, Cell Line, Tumor, Checkpoint Kinase 1, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Humans, Isoquinolines chemistry, Isoquinolines pharmacology, Mice, Mice, Nude, Molecular Conformation, Neoplasm Transplantation, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Pyrazines chemistry, Pyrazines pharmacology, Pyridines chemistry, Pyridines pharmacology, Stereoisomerism, Structure-Activity Relationship, Transplantation, Heterologous, Antineoplastic Agents chemical synthesis, Isoquinolines chemical synthesis, Protein Kinase Inhibitors chemical synthesis, Protein Kinases metabolism, Pyrazines chemical synthesis, Pyridines chemical synthesis
- 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.
- Published
- 2011
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