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Click to expand. Known microtubule binding sites for small molecule compounds.
Microtubule elongation following GTP-dependent tubulin dimer addition
Binds to αβ-tubulin dimers preventing assembly and promoting depolymerization.1
Binds to the colchicine binding site of β-tubulin, preventing αβ-tubulin dimer assembly.2,3
Rigidin C2 Cpd 7 *New*
Binds at Asn258 and Lys352 of β-tubulin and suppresses tubulin polymerization. Exhibits in vivo efficacy.4
Tubstat3 Cpd 21 *New*
Dual action, potent tubulin polymerization and STAT3 phosphorylation inhibitor.5
Shortening of microtubules by αβ-tubulin dimer removal
Binds and stabilizes tubulin dimers, prevents depolymerization and affects microtubule dynamics.6
Posttranslational modification affecting cargo trafficking
Deacetylase inhibitor that increases microtubule acetylation.7
Posttranslational modification essential for microtubule stabilization
Potent transglutaminase inhibitor.8
Microtubule Associating Proteins (MAPs)
Lattice binding MAPs that stabilize microtubules primarily in axons
Potently reduces Tau levels in vitro and ex vivo.9
Prevents MAP1,2 cleavage and degradation.10
Induces MAP1,2 protecolysis.10
Stabilizes and catalyzes tubulin dimer addition
Inhibits PP2A and affects DCx localization.11
γ-tubulin ring complex essential for microtubule nucleation during mitosis
Inhibits GSK-3β mediated γ-TuRC recruitment to spindle poles.12
Microtubule stabilization during spindle formation
Selective Aurora B kinase inhibitor inducing apoptosis and growth arrest.13
Specific Aurora B inhibitor causing apoptosis.13
Kinesin Spindle Protein (KSP)/Eg5/KIF11
Microtubule motor involved in mitotic pole separation
Inhibits kinesin Eg5 and alters its interaction with microtubules.14
Eg5 inhibitor that induces mitotic arrest.15
Motor protein that facilitates cargo transport and microtubule sliding in cilia/flagella
Interferes with dynein mediated motility in microtubules.16
Modulates interaction of motors to cargo the arrangement of microtubules
Protects microtubules from depolymerization. Recruits dynein-dynactin complex to centrosome.17,18
Facilitaes crosstalk betweek microtubules and actin
Noncompetitive inhibitor of Myosin II.19
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2. Lu, Y., Chen, J., Xiao, M., Li, W. & Miller, D. D. An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm. Res. 29, 2943–2971 (2012).
3. Colley, H. E. et al. An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer. J. Med. Chem. 58, 9309–9333 (2015).
4. Medellin, D. C. et al. Novel Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities. J. Med. Chem. 59, 480–485 (2016).
5. Lai, M.-J. et al. N -Sulfonyl-aminobiaryls as Antitubulin Agents and Inhibitors of Signal Transducers and Activators of Transcription 3 (STAT3) Signaling. J. Med. Chem. 58, 6549-58 (2015).
6. Verweij, J., Clavel, M. & Chevalier, B. Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind. Ann. Oncol. 5, 495–505 (1994).
7. Godena, V. K. et al. Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat. Commun. 5, 5245 (2014).
8. Lai, T. S. et al. Identification of Chemical Inhibitors to Human Tissue Transglutaminase by Screening Existing Drug Libraries. Chem. Biol. 15, 969–978 (2008).
9. Abisambra, J. et al. Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau. Biol. Psychiatry 74, 367–374 (2013).
10. Fifre, A. et al. Microtubule-associated protein MAP1A, MAP1B, and MAP2 proteolysis during soluble amyloid β-peptide-induced neuronal apoptosis: Synergistic involvement of calpain and caspase-3. J. Biol. Chem. 281, 229–240 (2006).
11. Schaar, B. T., Kinoshita, K. & McConnell, S. K. Doublecortin Microtubule Affinity Is Regulated by a Balance of Kinase and Phosphatase Activity at the Leading Edge of Migrating Neurons. Neuron 41, 203–213 (2004).
12. Izumi, N., Fumoto, K., Izumi, S. & Kikuchi, A. GSK-3beta regulates proper mitotic spindle formation in cooperation with a component of the gamma-tubulin ring complex, GCP5. J. Biol. Chem. 283, 12981–12991 (2008).
13. Yang, J. et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 110, 2034–2040 (2007).
14. Krzysiak, T. C. et al. A structural model for monastrol inhibition of dimeric kinesin Eg5. EMBO J. 25, 2263–2273 (2006).
15. Skoufias, D. A. et al. S-trityl-L-cysteine is a reversible, tight binding inhibitor of the human kinesin Eg5 that specifically blocks mitotic progression. J. Biol. Chem. 281, 17559–17569 (2006).
16. Lecland, N. & Lüders, J. The dynamics of microtubule minus ends in the human mitotic spindle. Nat. Cell Biol. 16, 770–8 (2014).
17. Nakamura, M. et al. Nordihydroguaiaretic acid, of a new family of microtubule-stabilizing agents, shows effects differentiated from paclitaxel. Biosci. Biotechnol. Biochem. 67, 151–157 (2003).
18. Arasaki, K., Tani, K., Yoshimori, T. & Stephens, D. Nordihydroguaiaretic acid affects multiple dynein-dynactin functions in interphase and mitotic cells. Mol. Pharmacol. 71, 454–460 (2007).
19. Bond, L. M., Tumbarello, D. a, Kendrick-Jones, J. & Buss, F. Small-molecule inhibitors of myosin proteins. Future Med. Chem. 5, 41–52 (2013).