5F4N

Multi-parameter lead optimization to give an oral CHK1 inhibitor clinical candidate: (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

Summary for 5F4N

• Entry DOI: 10.2210/pdb5f4n/pdb
• Descriptor: Serine/threonine-protein kinase Chk1, methyl 6-[(5-cyanopyrazin-2-yl)amino]-4-[[(2~{R})-morpholin-2-yl]methylamino]pyridine-3-carboxylate, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: inhibitor dna-damage chk1-potency herg-activity, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O14757
• Total number of polymer chains: 1
• Total formula weight: 32628.46

Authors

Collins, I.,Garrett, M.D.,van Montfort, R.,Osborne, J.D.,Matthews, T.P.,McHardy, T.,Proisy, N.,Cheung, K.J.,Lainchbury, M.,Brown, N.,Walton, M.I.,Eve, P.D.,Boxall, K.J.,Hayes, A.,Henley, A.T.,Valenti, M.R.,De Haven Brandon, A.K.,Box, G.,Westwood, I.M.,Jamin, Y.,Robinson, S.P.,Leonard, P.,Reader, J.C.,Aherne, G.W.,Raynaud, F.I.,Eccles, S.A. (deposition date: 2015-12-03, release date: 2016-05-25, Last modification date: 2024-05-08)

Primary citation

Osborne, J.D.,Matthews, T.P.,McHardy, T.,Proisy, N.,Cheung, K.M.,Lainchbury, M.,Brown, N.,Walton, M.I.,Eve, P.D.,Boxall, K.J.,Hayes, A.,Henley, A.T.,Valenti, M.R.,De Haven Brandon, A.K.,Box, G.,Jamin, Y.,Robinson, S.P.,Westwood, I.M.,van Montfort, R.L.,Leonard, P.M.,Lamers, M.B.,Reader, J.C.,Aherne, G.W.,Raynaud, F.I.,Eccles, S.A.,Garrett, M.D.,Collins, I.
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).
J.Med.Chem., 59:5221-5237, 2016

PubMed Abstract: 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.

PubMed: 27167172
DOI: 10.1021/acs.jmedchem.5b01938

Experimental method

X-RAY DIFFRACTION (1.91 Å)