Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery

Abstract

Microtubules are dynamic assemblies of ab-tubulin heterodimers and have been recognized as highly attractive targets for cancer chemotherapy. A broad range of agents bind to tubulin and interfere with microtubule assembly. Despite having a long history of characterization, colchicine binding site inhibitors (CBSIs) have not yet reached the commercial phase as anti-cancer drugs to date. We determined the structures of tubulin complexed with a set of structurally diverse CBSIs (lexibulin, nocodazole, plinabulin and tivantinib), among which nocodazole and tivantinib are both binary-function inhibitors targeting cancer-related kinases and microtubules simultaneously. High resolution structures revealed the detailed interactions between these ligands and tubulin. Our results showed that the binding modes of the CBSIs were different from previous docking models, highlighting the importance of crystal structure information in structurebased drug design. A real structure-based pharmacophore was proposed to rationalize key common interactions of the CBSIs at the colchicine domain. Our studies provide a solid structural basis for developing new anti-cancer agents for the colchicine binding site. DatabaseThe atomic coordinates and structure factors for tubulin complexed with lexibulin, nocodazole, plinabulin and tivantinib have been deposited in the Protein Data Bank under accession codes 5CA0, 5CA1, 5C8Y and 5CB4, respectively.

Synthesis, structure-activity relationships and biological evaluation of 7-phenyl-pyrroloquinolinone 3-amide derivatives as potent antimitotic agents

“…A relevant number of experimentally derived complex structures of colchicine binding site inhibitors (CBSI) were recently deposited in the Protein Data Bank (PDB) [17]. Interestingly, the superposition of the different crystal structures reveals a significant variability in the sidechains of the residues belonging to the colchicine site depending on the chemical nature of the ligand, as shown in SI_Fig.…”

Novel quinoline derivatives carrying nitrones/oximes nitric oxide donors: Design, synthesis, antiproliferative and caspase-3 activation activities

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Novel quinoline derivatives carrying nitrones and oxime as nitric oxide donors were prepared and characterized using different spectroscopic techniques. Several mechanisms can explain the anticancer effect of quinoline derivatives including: topoisomerase inhibition, [21][22][23] DNA intercalation, [24] protein kinases inhibition, [25][26][27] tubulin polymerase inhibition, [28][29][30][31] and induction of apoptosis. Antiproliferative screening results showed that the 2-benzylthioquinoline nitrones 6e and 6f and the 2-methylthio analogues 6g and 6h exhibited promising antiproliferative activity especially against leukemia and colon cancer cell lines.

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Pyridachlometyl has a novel anti‐tubulin mode of action which could be useful in anti‐resistance management

“…Although some anti‐tubulin agents, such as carbendazim, thiabendazole, and diethofencarb (Fig. ) and their analogs, have been used as agricultural fungicides for years, they are all classified as polymerization inhibitors, which target the colchicine site in β‐tubulin . On the contrary, the depolymerization of tubulin associated with the hydrolysis of GTP from GDP is also essential for cells .…”