1LD8

Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 49

Summary for 1LD8

• Entry DOI: 10.2210/pdb1ld8/pdb
• Related: 1JCQ 1LD7
• Related PRD ID: PRD_900003
• Descriptor: protein farnesyltransferase alpha subunit, protein farnesyltransferase beta subunit, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: alpha-alpha barrel, inhibitor, ftase, pftase, fpp, caax, ras, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 95032.86

Authors

Taylor, J.S.,Terry, K.L.,Beese, L.S. (deposition date: 2002-04-08, release date: 2002-06-19, Last modification date: 2023-08-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)