Tafetinib (SIM-010603) is a novel potent and orally available tyrosine kinase inhibitor with anti-angiogenic and anti-tumour activity.

Tafetinib, a promising multi-targeted receptor tyrosine kinase (RTK) inhibitor, is now being considered for evaluation in a phase clinical trial. In this work, the subchronic toxicity of Tafetinib in SD rats and beagle dogs has been characterized. Rats and dogs received Tafetinib orally (0-20 and 0-10mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 days following a 14-day recovery period. Sunitinib was used as a positive control. The No Observed Adverse Effect Level (NOAEL) of Tafetinib was 5mg/kg/day for rats, and undefined for dogs. The treatment resulted in unscheduled mortality in dogs receiving 10mg/kg of Tafetinib or Sunitinib. The adverse effects of Tafetinib on rats and dogs mainly included gastrointestinal toxicity, skeletal toxicity, myelosuppression, thymus atrophy, bronchopneumonia, cardiovascular dysfunction, and pancreatic toxicity. Similar observations have also been noted with this class of RTK signaling inhibitors and are consistent with pharmacologic perturbations of physiologic/angiogenic processes associated with the intended molecular targets. Most treatment-induced effects were reversible or showed ongoing recovery upon discontinuation of treatment. Tafetinib has shown a comparable toxicity effect on beagle dogs, while better tolerability on SD rats when compared to Sunitinib.[2]