4A50

Crystal structure of human kinesin Eg5 in complex with 2-Amino-5-(3-methylphenyl)-5,5-diphenylpentanoic acid

Summary for 4A50

• Entry DOI: 10.2210/pdb4a50/pdb
• Related: 1II6 1Q0B 1X88 1YRS 2FKY 2FL2 2FL6 2G1Q 2GM1 2UYI 2UYM 2WOG 2X2R 2X7C 2X7D 2X7E 2XAE 4A1Z 4A28 4A2T 4A51
• Descriptor: KINESIN-LIKE PROTEIN KIF11, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: cell cycle, mitosis, inhibitor, ksp
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P52732
• Total number of polymer chains: 1
• Total formula weight: 42226.01

Authors

Kaan, H.Y.K.,Kozielski, F. (deposition date: 2011-10-24, release date: 2012-10-31, Last modification date: 2023-12-20)

Primary citation

Wang, F.,Good, J.A.D.,Rath, O.,Kaan, H.Y.K.,Sutcliffe, O.B.,Mackay, S.P.,Kozielski, F.
Triphenylbutanamines: Kinesin Spindle Protein Inhibitors with in Vivo Antitumor Activity.
J.Med.Chem., 55:1511-, 2012

PubMed Abstract: The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit K(i)(app) ≤ 10 nM and GI(50) ≈ 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.

PubMed: 22248262
DOI: 10.1021/JM201195M

Experimental method

X-RAY DIFFRACTION (2.75 Å)