Colcemid (Demecolcine), a derivative of colchicine, is a potent mitotic inhibitor[1][2]. Colcemid binds to the protein tubulin and arrest cells in metaphase for karyotyping assays. Colcemid incuces cell apoptosis and can be used for cancer research[2].
Indibulin (ZIO 301) , an orally applicable inhibitor of tubulin assembly, shows potent anticancer activity with a minimal neurotoxicity. Indibulin reduces inter-kinetochoric tension, produces aberrant spindles, activates mitotic checkpoint proteins Mad2 and BubR1, and induces mitotic arrest and apoptosis[1].
Podophyllotoxin is a potent inhibitor of microtubule assembly and DNA topoisomerase II.IC50 Value:Target: Topoisomerase II; Microtubule/TubulinPodophyllotoxin, a kind of non-alkaloid toxin lignan extracted from the roots and rhizomes of Podophyllum plant, has been shown to inhibit the growth of various carcinoma cells. Podophyllotoxin is a natural product that inhibits the polymerization of tubulin and has served as a prototype for the development of diverse antitumor agents in clinical use.
Ganoderic acid T-Q (Ganodermic acid T-Q) (compound 1) is a natural product that can be found in ganoderma lucidum. Ganoderic acid T-Q stimulates tubulin polymerization[1].
Tubulysin E is a highly cytotoxic peptide isolated from the myxobacterial species Archangium geophyra and Angiococcus disciformis. Tubulysin displays extremely potent cytotoxic activity in mammalian cells, including multidrug-resistant cell lines, with IC50 values in the lower nanomolar range[1]. Tubulysin E is a cytotoxic activity tubulysin which inhibits tubulin polymerization and leads to cell cycle arrest and apoptosis[2].
ELR510444 is a novel microtubule disruptor; inhibits MDA-MB-231 cell proliferation with IC50 of 30.9 nM; not a substrate for the P-glycoprotein drug transporter and retains activity in βIII-tubulin-overexpressing cell lines.IC50 value: 30.9 nM(MDA-MB-231 cell) [1]Target: Microtubule disruptorELR510444 is not a substrate for the P-glycoprotein drug transporter and retains activity in βIII-tubulin-overexpressing cell lines, suggesting that it circumvents both clinically relevant mechanisms of drug resistance to this class of agents. ELR510444 also shows potent antitumor activity in the MDA-MB-231 xenograft model with at least a 2-fold therapeutic window. Studies in tumor endothelial cells show that a low concentration of ELR510444 (30 nM) rapidly alters endothelial cell shape, similar to the effect of the vascular disrupting agent combretastatin A4. ELR510444 is a novel microtubule-disrupting agent with potential antivascular effects and in vivo antitumor efficacy [1]. ELR510444 decreased HIF-1α and HIF-2α levels, reduced RCC cell viability and clonogenic survival, and induced apoptosis. VHL-deficient RCC cells were more sensitive to ELR510444-mediated apoptosis and restoration of VHL promoted drug resistance. Higher concentrations of ELR51044 promoted apoptosis independently of VHL status, possibly due to the microtubule destabilizing properties of this agent. ELR510444 significantly reduced tumor burden in the 786-O and A498 RCC xenograft models [2].
Taccalonolide A is a microtubule stabilizer, which is a steroid isolated from Tacca chantrieri, with cytotoxic and antimalarial activities[1][2]. Taccalonolide A causes G2-M accumulation, Bcl-2 phosphorylation and initiation of apoptosis[1]. Taccalonolide A is effective in vitro against cell lines that overexpress P-glycoprotein (Pgp) and multidrug resistance protein 7 (MRP7), with an IC50 of 622 nM for SK-OV-3 cells[3].
DHA-paclitaxel is an inert prodrug composed of the natural fatty acid DHA covalently linked to the C2'-position of paclitaxel. The paclitaxel moiety binds to tubulin and inhibits the disassembly of microtubules, thereby resulting in the inhibition of cell division. Compared to Paclitaxel, DHA-Paclitaxel targets tumor cells more specifically because tumor cells absorb large amounts of natural fatty acids for use as biochemical precursors and energy sources.
Plinabulin (NPI-2358) is a vascular disrupting agents (VDA) against tubulin-depolymerizing with IC50 of 9.8~18 nM in tumor cells.IC50 Value: 9.8~18 nMTarget: Microtubule/Tubulinin vitro: NPI-2358 binds to the colchicine-binding site of tubulin and has potent inhibitory to human tumor cell lines which have overexpressed Pgp or reduced nuclear Topo II catalytic activity, with IC50 from 9.8 to 18 nM. NPI-2358 is able to rapidly induce tubulin depolymerization in HUVECs and monolayer permeability even at 20 nM. NPI-2358 induces cell death in MM cells with IC50 of 8-10 nM, which due to trigger early mitotic arrest in MM cells. NPI-2358 also inhibits tubule formation and migration of endothelial as well as MM cells, which leads to disrupt tumor vasculature. NPI-2358 could induces cell death in patient MM (CD138+) cells without effecting viability of normal mononuclear cells. Blockade of JNK abrogates NPI-2358-induced mitotic arrest or MM cell death. in vivo: NPI-2358 (7.5 mg/kg) inhibits tumor growth in human plasmacytoma mouse xenograft models at well-tolerated doses. NPI-2358 induces a time- and dose-dependent decrease in tumour perfusion. NPI-2358 is more sensitive to the KHT sarcoma than the C3H tumour, while radiation response could enhance the antitumor activity in both models.
Eribulin mesylate is a microtubule targeting agent that is used in the treatment of metastatic breast cancer. It inhibits the proliferation of cancer cells by binding microtubule proteins and microtubules.
Tubulin polymerization-IN-9 is a potent tubulin inhibitor with IC50 of 1.82 μM. Tubulin polymerization-IN-9 causes cell cycle arrest at G2/M phase, and induces cell apoptosis and depolarized mitochondria of K562 cells. Tubulin polymerization-IN-9 has potent anti-vascular and antitumor activities[1].
Vc-MMAD consists the ADCs linker(Val-Cit) and potent tubulin inhibitor (MMAD), Vc-MMAD is an antibody drug conjugate.IC50 Valu: N/ATarget: tubulin; ADCsMonomethyl auristatin D (MMAD), a potent tubulin inhibitor, is a toxin payload and antibody drug conjugate.For comparison purposes, the ADC A1 -mc-MMAD and/or A1 -vc-MMAD were used. The linker payload, mc-MMAD (6-maleimidocaproyl-monomethylauristatin-D) was conjugated to the A1 anti-5T4 monoclonal antibody through a cysteine residue at a ratio of approximately 4 drug moieties per antibody molecule. The linker payload mc- Val-Cit-PABA-MMAD or vc-MMAD (maleimidocapronic -valine-citruline-p- aminobenzyloxycarbonyl- monomethylauristatin-D) was conjugated to the A1 anti-5T4 monoclonal antibody through a cysteine residue at a ratio of approximately 4 drug moieties per antibody molecule (Antibody-drug conjugates Patent: WO 2013068874 A1).
Auristatin F is a cytotoxic tubulin modifier with potent and selective antitumor activity; MMAF analog and cytotoxin in Antibody-drug conjugates.
BTB-1 is a potent, selective and reversible mitotic motor protein Kif18A inhibitor with an IC50 of 1.69 μM.
Amphethinile is an anti-tubulin agent. The affinity constant for the association (Ka) of Amphethinile with tubulin is 1.3 μM.
Tubulin polymerization-IN-30 (compound 6e) is a potent Tubulin polymerization inhibitor. Tubulin polymerization-IN-30 is a colchicine binding site inhibitor. Tubulin polymerization-IN-30 can disrupt intracellular microtubule organization, arrest cell cycle at the G2/M phase. Tubulin polymerization-IN-30 exhibits the high potency against the cancer cell lines including SGC-7901, A549 and HeLa, with IC50 values of 2.16, 2.21, and 0.403 μM[1].
Wikstrol A is a potent antifungal, antimitotic and anti-HIV-1 Agent. Wikstrol A induces morphological deformation of P. oryzae mycelia with an MMDC value of 70.1 µM. Wikstrol A shows activity against microtubule polymerization with an IC50 value of 131 µM. Wikstrol A shows anti-HIV-1 activity with an IC50 value of 67.8 µM[1].
Taltobulin trifluoroacetate (HTI-286; SPA-110) is an analogue of Hemiasterlin; potent tubulin inhibitor; ADCs cytotoxin.IC50 value:Target: tubulinin vitro: HTI-286 significantly inhibited proliferation of all three hepatic tumor cell lines (mean IC50 = 2 nmol/L +/- 1 nmol/L) in vitro. Interestingly, no decrease in viable primary human hepatocytes (PHH) was detected under HTI-286 exposure [1]. In all cell lines tested, HTI-286 was a potent inhibitor of proliferation and induced marked increases in apoptosis. Despite similar transcriptomic changes regarding cell death and cell cycle regulating genes after exposure to HTI-286 or docetaxel, array analysis revealed distinct molecular signatures for both compounds [2].in vivo: Intravenous administration of HTI-286 significantly inhibited tumor growth in vivo (rat allograft model) [1]. HTI-286 significantly inhibited growth of PC-3 and LNCaP xenografts and retained potency in PC-3dR tumors. Simultaneous castration plus HTI-286 therapy was superior to sequential treatment in the LNCaP model [2].
KIF18A-IN-4 is a moderately potent ATP and microtubule (MT) noncompetitive KIF18A inhibitor (IC50=6.16 μM). KIF18A-IN-4 has selectivity against a large panel of mitotic kinesins and kinases, and does not show any direct effects on tubulin assembly. KIF18A-IN-4 exhibits anti-tumor activity[1].
Tubulin polymerization-IN-52 (compound SC23) is a potent tubulin polymerization inhibitor, with an IC50 of 2.9 μM[1].
Sertaconazole (FI7056 free base) is a broad-spectrum topical antifungal agent, exhibits anti-inflammatory activity via activation of a p38-COX-2-PGE2 pathway. Sertaconazole is also a microtubule inhibitor, shows antiproliferative effect, induces apoptosis and autophagy, and can also inhibit the migration of cells[1][2][3][4].
SS28, a SRT501 analog with oral bioavailability, inhibits tubulin polymerization to cause cell cycle arrest at G2/M phase. SS28 results in apoptosis rather than necrosis tubulin[1].
Monomethyl auristatin D (MMAD), a potent tubulin inhibitor, is a toxin payload in antibody drug conjugate; Mc-MMAD is a protective group (maleimidocaproyl) -conjugated MMAD.IC50 Value:Target: tubulin; ADCsFor comparison purposes, the ADC A1 -mc-MMAD and/or A1 -vc-MMAD were used. The linker payload, mc-MMAD (6-maleimidocaproyl-monomethylauristatin-D) was conjugated to the A1 anti-5T4 monoclonal antibody through a cysteine residue at a ratio of approximately 4 drug moieties per antibody molecule. The linker payload mc- Val-Cit-PABA-MMAD or vc-MMAD (maleimidocapronic -valine-citruline-p- aminobenzyloxycarbonyl- monomethylauristatin-D) was conjugated to the A1 anti-5T4 monoclonal antibody through a cysteine residue at a ratio of approximately 4 drug moieties per antibody molecule (Antibody-drug conjugates Patent: WO 2013068874 A1).
Cryptophycin 1 is a potent cytotoxic antimicrotubule agent which is isolated from Nostoc sp. Cryptophycin 1 can induce cells apoptosis, and exhibits antitumor activity and exceptional antiproliferative potency[1][2][3].
Estramustine phosphate, an estradiol analog, is an orally active antimicrotubule chemotherapy agent. Estramustine phosphate depolymerises microtubules by binding to microtubule associated proteins (MAPs) and/or to tubulin. Estramustine phosphate can interfere mitosis, trigger cell death and induce apoptosis, which can be used for the research of cancer like prostate cancer[1][2][3].
MY-673 is a colchicine binding site inhibitor (CBSI), that inhibits tubulin polymerization. MY-673 inhibits the ERK signaling pathway, which in turn affects SMAD4 protein expression levels in the TGF-β/SMAD pathway. MY-673 inhibited cell proliferation, migration and induced apoptosis in vivo and in vitro[1].
Novel irreversible transglutaminase 2 (TG2) inhibitor
Cemadotin (LU103793) is an analogue of Dolastatin 15 (HY-P1126) which is naturally occurring cytotoxic peptides. Cemadotin blocks cells at mitosis, and exhibits Ki value of 1 μM for inhibiting tubulin. Cemadotin can be used to research anticancer[1].
Tubulin polymerization-IN-37 is a tubulin polymerization inhibitor (IC50: 2.3 μΜ). Tubulin polymerization-IN-37 binds to the colchicine site of tubulin and inhibits colchicine binding. Tubulin polymerization-IN-37 can be used in the research of cancers, such as lymphomas[1].
Epothilone E is a related compound of epothilone, which inhibits microtubule protein function and blocks cell division, and has anti-tumor activity[1].