1ld8
From Proteopedia
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'''Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 49''' | '''Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 49''' | ||
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[[Category: Taylor, J S.]] | [[Category: Taylor, J S.]] | ||
[[Category: Terry, K L.]] | [[Category: Terry, K L.]] | ||
| - | [[Category: | + | [[Category: Alpha-alpha barrel]] |
| - | [[Category: | + | [[Category: Caax]] |
| - | [[Category: | + | [[Category: Fpp]] |
| - | [[Category: | + | [[Category: Ftase]] |
| - | [[Category: | + | [[Category: Inhibitor]] |
| - | [[Category: | + | [[Category: Pftase]] |
| - | [[Category: | + | [[Category: Ra]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 23:48:26 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 20:48, 2 May 2008
Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 49
Overview
A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.
About this Structure
1LD8 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency., Bell IM, Gallicchio SN, Abrams M, Beese LS, Beshore DC, Bhimnathwala H, Bogusky MJ, Buser CA, Culberson JC, Davide J, Ellis-Hutchings M, Fernandes C, Gibbs JB, Graham SL, Hamilton KA, Hartman GD, Heimbrook DC, Homnick CF, Huber HE, Huff JR, Kassahun K, Koblan KS, Kohl NE, Lobell RB, Lynch JJ Jr, Robinson R, Rodrigues AD, Taylor JS, Walsh ES, Williams TM, Zartman CB, J Med Chem. 2002 Jun 6;45(12):2388-409. PMID:12036349 Page seeded by OCA on Fri May 2 23:48:26 2008
Categories: Homo sapiens | Protein complex | Beese, L S. | Taylor, J S. | Terry, K L. | Alpha-alpha barrel | Caax | Fpp | Ftase | Inhibitor | Pftase | Ra
