1LD7

Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 66

1LD7 の概要

• エントリーDOI: 10.2210/pdb1ld7/pdb
• 関連するPDBエントリー: 1JCQ 1LD8
• 関連するBIRD辞書のPRD_ID: PRD_900003
• 分子名称: protein farnesyltransferase alpha subunit, protein farnesyltransferase beta subunit, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: alpha-alpha barrel, inhibitor, ftase, pftase, fpp, caax, ras, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 94930.81

構造登録者

Taylor, J.S.,Terry, K.L.,Beese, L.S. (登録日: 2002-04-08, 公開日: 2002-06-19, 最終更新日: 2023-08-16)

主引用文献

Bell, I.M.,Gallicchio, S.N.,Abrams, M.,Beese, L.S.,Beshore, D.C.,Bhimnathwala, H.,Bogusky, M.J.,Buser, C.A.,Culberson, J.C.,Davide, J.,Ellis-Hutchings, M.,Fernandes, C.,Gibbs, J.B.,Graham, S.L.,Hamilton, K.A.,Hartman, G.D.,Heimbrook, D.C.,Homnick, C.F.,Huber, H.E.,Huff, J.R.,Kassahun, K.,Koblan, K.S.,Kohl, N.E.,Lobell, R.B.,Lynch Jr., J.J.,Robinson, R.,Rodrigues, A.D.,Taylor, J.S.,Walsh, E.S.,Williams, T.M.,Zartman, C.B.
3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency.
J.Med.Chem., 45:2388-2409, 2002

PubMed Abstract: 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.

PubMed: 12036349
DOI: 10.1021/jm010531d

実験手法

X-RAY DIFFRACTION (2 Å)