A consortium of research groups in collaboration with the company BeyondSpring Pharmaceuticals Inc. and with the participation of the group of Microtubule Stabilizing Agents led by Dr. Fernando Díaz at Centro de Investigaciones Biológicas, has just shown that the plinabulin -a compound of this company currently in clinical phase III as an antitumor - shows specificity for one of the tubulin isotypes.
One of the main problems of chemotherapy is the development of resistance to treatment. Inhibition of tubulin function is a broad-spectrum treatment against tumors that are not sensitive to specific treatments. However, and although tumor cells lack the ability of bacteria and viruses to respond quickly to chemical agents with mutations at the site of drug binding, in the case of antitumor chemotherapy based on tubulin inhibition it has been observed that isotypes other than this protein may be expressed that are less sensitive to a particular drug, which makes necessary to develop specific compounds of the specific isoform of tubulin.
The work of La Sala et al. has shown by x-ray crystallography that the plinabulin adopts the same binding mode with the two tubulin isoforms studied, αβII and αβIII, although additionally this drug also interacts with two residues that differ according to the isoform considered. Dr. Díaz's group at CIB performed biochemical tests that have shown that plinabulin selectively inhibits the αβII isotype over αβIII, as predicted by structural and bioinformatics studies.
Since the overexpression of tubulin αβIII confers tumor resistance to classical agents targeting tubulin such as vinblastine and vincristine, the discovery recently published in the journal Chem marks a potential short-term therapeutic use for plinabulin.
Reference: Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes. Giuseppina La Sala, Natacha Olieric, Ashwani Sharma, Federica Viti, Francisco de Asis Balaguer Perez, Lan Huang, James R. Tonra, G. Kenneth Lloyd, Sergio Decherchi, José Fernando Díaz, Michel O. Steinmetz, Andrea Cavalli (2019) Chem, Volume 5, Issue 11, Pages 2969-2986.
More info: link.