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2hy0
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Through a comparison of X-ray co-crystallographic data for 1 and 2 in the | + | Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds. |
==About this Structure== | ==About this Structure== | ||
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[[Category: kinase]] | [[Category: kinase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:47:03 2008'' |
Revision as of 15:47, 21 February 2008
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crystal structure of chek1 in complex with inhibitor 22
Overview
Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.
About this Structure
2HY0 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
Reference
Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors., Huang S, Garbaccio RM, Fraley ME, Steen J, Kreatsoulas C, Hartman G, Stirdivant S, Drakas B, Rickert K, Walsh E, Hamilton K, Buser CA, Hardwick J, Mao X, Abrams M, Beck S, Tao W, Lobell R, Sepp-Lorenzino L, Yan Y, Ikuta M, Murphy JZ, Sardana V, Munshi S, Kuo L, Reilly M, Mahan E, Bioorg Med Chem Lett. 2006 Nov 15;16(22):5907-12. Epub 2006 Sep 20. PMID:16990002
Page seeded by OCA on Thu Feb 21 17:47:03 2008
