title: Optimized S-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models.
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.
authors: Molecular Motors Laboratory, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK. james.good@chem.umu.se
authors: James A D
authors: JA
authors: Good
authors: Fang
authors: F
authors: Wang
authors: Oliver
authors: O
authors: Rath
authors: Hung Yi Kristal
authors: HY
authors: Kaan
authors: Sandeep K
authors: SK
authors: Talapatra
authors: Dawid
authors: D
authors: Podgórski
authors: Simon P
authors: SP
authors: MacKay
authors: Frank
authors: F
authors: Kozielski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D002082:Butylamines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011799:Quinazolines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002082:Butylamines; D002867:Chromones; D011799:Quinazolines; C557279:SB 743921; C003724:3-tritylthio-L-alanine; C508757:ispinesib; C521052:Kif11 protein, mouse; D016547:Kinesins; D003545:Cysteine
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