| 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). |
| Authors: |
Osborne, JD; Matthews, TP; McHardy, T; Proisy, N; Cheung, K-MJ; Lainchbury, M; Brown, N; Walton, MI; Eve, PD; Boxall, KJ; Hayes, A; Henley, AT; Valenti, MR; De Haven Brandon, AK; Box, G; Jamin, Y; Robinson, SP; Westwood, IM; van Montfort, RLM; Leonard, PM; Lamers, MBAC; Reader, JC; Aherne, GW; Raynaud, FI; Eccles, SA; Garrett, MD; Collins, I |
| Contributors: |
Matthews, Thomas; McHardy, Tatiana; Jamin, Yann; Robinson, Simon; Van Montfort, Robert; Raynaud, Florence; Collins, Ian |
| Publisher Information: |
AMER CHEMICAL SOC |
| Publication Year: |
2016 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Subject Terms: |
Humans; 4-Aminopyridine; Pyrazines; Protein Kinase Inhibitors; Molecular Structure; Structure-Activity Relationship; Dose-Response Relationship; Drug; Models; Molecular; Checkpoint Kinase 1 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print-Electronic; 5237; application/pdf |
| Language: |
English |
| ISSN: |
1520-4804; 0022-2623 |
| Relation: |
Journal of medicinal chemistry, 2016, 59 (11), pp. 5221 - 5237; https://repository.icr.ac.uk/handle/internal/46 |
| DOI: |
10.1021/acs.jmedchem.5b01938 |
| Availability: |
https://doi.org/10.1021/acs.jmedchem.5b01938; https://repository.icr.ac.uk/handle/internal/46 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.F369CA00 |
| Database: |
BASE |