Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2
Hilton, S; Naud, S; Caldwell, JJ; Boxall, K; Burns, S; Anderson, VE; Antoni, L; Allen, CE; Pearl, LH; Oliver, AW; Wynne Aherne, G; Garrett, MD; Collins, I
| HERO ID | 1466693 |
|---|---|
| In Press | No |
| Year | 2010 |
| Title | Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2 |
| Authors | Hilton, S; Naud, S; Caldwell, JJ; Boxall, K; Burns, S; Anderson, VE; Antoni, L; Allen, CE; Pearl, LH; Oliver, AW; Wynne Aherne, G; Garrett, MD; Collins, I |
| Journal | Bioorganic & Medicinal Chemistry |
| Volume | 18 |
| Issue | 2 |
| Page Numbers | 707-718 |
| Abstract | 5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were identified from high throughput screening of a kinase-focussed compound library. Rapid exploration of the hits through straightforward chemistry established structure-activity relationships and a proposed ATP-competitive binding mode which was verified by X-ray crystallography of several analogues bound to CHK2. Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and dioxane groups which improved the affinity and the selectivity of the compounds for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be successfully replaced by acyclic omega-aminoalkylamides, which made additional polar interactions within the binding site and led to more potent inhibitors of CHK2. Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2. |
| Doi | 10.1016/j.bmc.2009.11.058 |
| Pmid | 20022510 |
| Wosid | WOS:000273613500023 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Source: Web of Science WOS:000273613500023 |
| Is Public | Yes |
| Language Text | English |
| Keyword | CHK2; Kinase inhibitor; High-throughput screening; Crystallography |