Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin : An Approach to Targeting Tumor Growth (Perspective)

The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ- tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).Due to the amount of original research articles and reviews on this subject, we were unable to cite all of them; any omissions were unintentional. Author’s research in this subject has been financed by the Spanish Ministerio de Economıá y Competitividad (SAF2012-39760-C02-01 and SAF2015-64629-C2- 1-R (MINECO-FEDER) to M.-J.P.-P. and E.-M.P.) and Comunidad de Madrid (BIPEDD2; ref P2010/BMD-2457). S.L. and M.-J.P.-P. acknowledge networking contribution by COST Action CM1407 “Challenging organic synthesis inspired by nature-from natural products chemistry to drug discovery”. M.-D.C. thanks the Fondo Social Europeo (FSE) and the JAE Predoc Programme for a predoctoral fellowship.Peer reviewe

Blocking blood flow to solid tumors by destabilizing tubulin: An approach to targeting tumor growth

The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).status: publishe