page_title: Discovery and development of tubulin inhibitors
section_title: Mechanism of action
hierarchical_section_title: Discovery and development of tubulin inhibitors / Mechanism of action
caption_attribution_description: English: Tubulin inhibitors binding site
context_page_description: Tubulin inhibitors are chemotherapy drugs that interfere directly with the tubulin system, which is in contrast to those chemotherapy drugs acting on DNA. Microtubules play an important role in eukaryotic cells. Alpha- and beta-tubulin, the main components of microtubules, have gained considerable interest because of their function and biophysical properties and has become the subject of intense study. The addition of tubulin ligands can affect microtubule stability and function, including mitosis, cell motion and intracellular organelle transport. Tubulin binding molecules have generated significant interest after the introduction of the taxanes into clinical oncology and the general use of the vinca alkaloids. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization or depolymerization into the microtubules. This mode of action is also shared with another natural agent called colchicine.
context_section_description: Agents which act as inhibitors of tubulin, also act as inhibitors of cell division. 
  A microtubule exists in a continuous dynamic state of growing and shortening by reversible association and dissociation of α/β-tubulin heterodimers at both the ends. This dynamic behavior and resulting control over the length of the microtubule is vital to the proper  functioning of the mitotic spindle in mitosis i.e., cell division.
  Microtubule is involved in different stages of the cell cycle. During the first stage or prophase, the microtubules required for cell division begins to form and grow towards the newly formed chromosomes forming a bundle of microtubules called the mitotic spindle. During prometaphase and metaphase this spindle attaches itself to the chromosomes  at a particular point called the kinetochore and undergoes several growing and shortening periods in tuning  with the  back and forth oscillations of the chromosomes. In anaphase also, the microtubules attached to the chromosomes  maintain a carefully regulated shortening and lengthening process. Thus the presence of a drug which can suppress the microtubule dynamics is sufficient to block the cell cycle and result in the death of the cells by apoptosis.
  Tubulin inhibitors thus act by interfering with the dynamics of the microtubule, i.e., growing (polymerization) and shortening (depolymerization). One class of inhibitors operate by inhibiting polymerization of tubulin to form microtubules  and are called polymerization inhibitors like the colchicine analogues and the vinca alkaloids. They decrease the microbule polymer mass in the cells at high concentration and act as microtubule-destabilizing agents. The other class of inhibitors operate by inhibiting the depolymerization of polymerized tubulin and increases the microtubule polymer mass in the cells. They  act as microbule-stabilizing agents and  are called depolymerization inhibitors like the paclitaxel analogues. These three classes of drugs seems to operate by slightly different mechanism.
  Colchicine analogues blocks cell division by disrupting the microtubule. It has been reported that the β-subunit of tubulin is involved in colchicine binding. It binds to the soluble tubulin to form colchicine-tubulin complex.  This complex along  with the normal tubulins then undergoes polymerization to form  the microtubule. However the presence of this T-C complex prevents further polymerization of the microtubule . This complex brings about a conformational change which blocks the tubulin dimers  from further addition and thereby prevents the growth of the microtubule. As the T-C complex slows down the addition of new dimers, the microtubule disassembles due to structural imbalance or instability during the metaphase of mitosis.
  The Vinca alkaloids bind to the β-subunit of tubulin dimers at a distinct region called the Vinca-binding domain. They bind to tubulin rapidly, and this binding is reversible and independent of temperature (between 0 °C and 37 °C). In contrast to colchicine, vinca alkaloids bind to the microtubule directly. They do not first form a complex  with the soluble tubulin nor do they  copolymerize to form the microtubule, however they are capable of bringing about a conformational change in tubulin in connection with tubulin self-association. Vinca alkaloids bind to the tubulin with high affinity at the microtubule ends but with low affinity at the tubulin sites present along the sides of the microtubule cylinder. The binding of these drugs at the high affinity sites results in strong kinetic  suppression of tubulin exchange even at low drug concentration while their  binding to the low affinity sites in relatively high drug concentration depolymerizes microtubules.
  In contrast to colchicine and vinca alkaloids, paclitaxel enhances microtubule polymerization promoting both the nucleation and elongation phases of the polymerization reaction, and it reduces the critical  tubulin sub-unit concentration (i.e., soluble tubulin concentration at steady- state). Microtubules polymerized in presence of paclitaxel
caption: Tubulin inhibitors binding site[10]
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