Tubulin/microtubule-binding properties of MTIs
Property | MTI class | ||
---|---|---|---|
Vinca alkaloids | Taxanes-paclitaxel | epothilones-ixabepilone | |
Mechanism of action | • Direct binding to β-subunit of α/β-tubulin dimers | • Direct binding to β-subunit of α/β-tubulin dimers | • Direct binding to β-subunit of α/β-tubulin dimers |
Binding site | • Binds to β-tubulin at site near exchangeable GTP-binding site | • β-tubulin binding site located near inter microtubule protofilament contacts | • Overlaps paclitaxel binding site on β-tubulin |
• Two distinct binding sites on microtubules | • Does not overlap binding sites for GTP, colchicine, podophyllotoxin, or vincas | • Epothilones competitively inhibit binding of paclitaxel to β-tubulin | |
• High affinity binding at microtubule ends | • Poor binding to soluble tubulin | • High affinity binding to polymerized tubulin | |
• Low affinity binding along microtubule surface | • High affinity binding to polymerized tubulin | • Thr274, Arg282, Glu292, and Ala231 play essential roles in epothilone binding | |
• Phe270 and Ala364 play essential roles in taxane binding | |||
Biochemical effect(s) | • Suppress microtubule dynamics | • Suppress microtubule dynamics | • Suppress microtubule dynamics |
• Suppress microtubule assembly | • Enhance microtubule assembly | • Enhance microtubule assembly | |
• Induce microtubule depolymerization | • Induce tubulin polymerization | • Induce tubulin polymerization | |
• Suppress microtubule treadmilling | • Suppress microtubule treadmilling | • Suppress microtubule treadmilling | |
• Suppress microtubule dynamic instability | • Suppress microtubule dynamic instability | • Suppress microtubule dynamic instability | |
• Induce tubulin association into coiled spiral aggregates | • Induce microtubule bundling | • Induce microtubule bundling | |
• Decrease polymer mass at high concentrations | • Induce formation of multipolar spindles | • Induce formation of multipolar spindles | |
• Increase polymer mass at high concentrations | • Increase polymer mass at high concentrations | ||
Selectivity | • No difference in β-tubulin isotype binding affinity | • Selective binding and inactivation of βII-tubulin containing microtubules | • Broad selectivity for microtubules containing multiple β-tubulin isotypes |
• Higher affinity for α/βII and α/βIII tubulin dimers in the presence of GTP observed for vincristine | • Not active against βIII and βIV-tubulin containing microtubules | • Active against βIII and βIV-tubulin containing microtubules | |
• Do not stabilize microtubules in Saccharomyces cerevisiae | • Stabilize microtubules in S. cerevisiae cells | ||
• Substrates for drug efflux transporters such as P-gp | • Are not substrates for drug efflux transporters such as P-gp |
NOTE: See refs. 3, 5, 7, 8, 31, 34, 35, 42, 85, 86.