4BBG

Crystal structure of human kinesin Eg5 in complex with 3-(((2-Aminoethyl)sulfanyl)(3-ethylphenyl) phenylmethyl)phenol

Summary for 4BBG

• Entry DOI: 10.2210/pdb4bbg/pdb
• Related: 1II6 1Q0B 1X88 1YRS 2FKY 2FL2 2FL6 2G1Q 2GM1 2UYI 2UYM 2WOG 2X2R 2X7C 2X7D 2X7E 2XAE 4A1Z 4A28 4A50 4A51 4A5Y 4AP0 4AQV 4AQW 4AS7 4B7B
• Descriptor: KINESIN-LIKE PROTEIN KIF11, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: cell cycle, mitosis, inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P52732
• Total number of polymer chains: 1
• Total formula weight: 42047.87

Authors

Kaan, H.Y.K.,Kozielski, F. (deposition date: 2012-09-22, release date: 2013-05-15, Last modification date: 2023-12-20)

Primary citation

Good, J.A.D.,Wang, F.,Rath, O.,Kaan, H.Y.K.,Talapatra, S.K.,Podgorski, D.,Mackay, S.P.,Kozielski, F.
Optimized S-Trityl-L-Cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models.
J.Med.Chem., 56:1878-, 2013

PubMed Abstract: The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K(i)(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacokinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.

PubMed: 23394180
DOI: 10.1021/JM3014597

Experimental method

X-RAY DIFFRACTION (2.75 Å)