Anti-microtubule 'plinabulin' chemical probe KPU-244-B3 labeled both alpha- and beta-tubulin.
Plinabulin (1, NPI-2358), a potent microtubule-targeting agent derived from the natural diketopiperazine 'phenylahistin' with a colchicine-like tubulin depolymerization activity, is an anticancer agent undergoing Phase II clinical trials in four countries including the United States. In order to understand the precise binding mode of plinabulin with tubulin, a new bioactive biotin-tagged photoaffinity probe 4 (KPU-244-B3) was designed and synthesized. Probe 4 showed significant binding affinity to tubulin in a binding assay, and selectively bound to tubulin in an HT-1080 cell lysate without photo-irradiation. In a tubulin photoaffinity labeling study, probe 4 labeled both alpha- and beta-tubulin subunits and these interactions were competitively inhibited by plinabulin during photo-irradiation. These results suggest that plinabulin binds in the boundary region between alpha- and beta-tubulin near the colchicine binding site, and not inside the colchicine binding cavity.
Yamazaki
Yuri
Y
Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
Sumikura
Makiko
M
Hidaka
Koushi
K
Yasui
Hiroyuki
H
Kiso
Yoshiaki
Y
Yakushiji
Fumika
F
Hayashi
Yoshio
Y
D001667:Binding, Competitive; D015153:Blotting, Western; D045744:Cell Line, Tumor; D054659:Diketopiperazines; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019920:Photoaffinity Labels / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry* / Q000187:drug effects
D054659:Diketopiperazines; D007093:Imidazoles; C551970:KPU-244-B3; C514351:NPI 2358; D019920:Photoaffinity Labels; D010879:Piperazines; D010880:Piperidines; D014404:Tubulin