1ld8

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spinqualitylabelsall models 1ld8, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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 with , , , and as ligands. 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

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