Preclinical toxicology of alofanib, an allosteric inhibitor of fibroblast growth factor receptor 2

Abstract

Background. Inhibition of fibroblast growth factor receptor type 2 (FGFR2) appears to be appropriate in patients with tumors expressing or amplifying FGFR2. The toxicity of allosteric FGFR2 inhibitors has not been previously studied. Purpose. Evaluation of the toxicity of the anticancer drug alofanib (RPT835), allosteric inhibitor of fibroblast growth factor receptor 2 type (FGFR2), in standard experimental in-vivo models in rodents and non-rodents. Material and methods . The general toxic effect of the alofanib was studied in an acute and chronic experiment on outbred animals (rats and rabbits) of both sexes. An experimental study was conducted in accordance with the ethical principles of handling laboratory animals. Results. The assumption that inhibition of FGFR2 provides a low level of toxicity has been proved. It was established that alofanib belongs to the 4 class of low-toxic chemical substances according to the classification of hazard levels of toxic effects of drugs and to the low-risk drugs by the value of the index of the therapeutic action, as well as to the 3 class (low-toxic drugs) according to the class of hazards for clinical application. Alofanib doesn»t cause allergenic and immunotoxic effects as well as doesn»t have pyrogenic properties. Increase of phosphates level (class-specific adverse effect of FGFR2 inhibitors) was statistically significant but less evident. During the study was noticed such an adverse effect as inhibition of spermatogenesis. Conclusion. Alofanib belongs to the classes of low-hazard and low-toxic chemicals and can be studied in a clinical study.