The new therapeutic option is pivotal due to the restricted efficacy of current treatments (surgery, radioactive iodine treatment, and chemotherapy) in progressive thyroid carcinomas. Gain-of-function mutations of the receptor tyrosine kinase RET have been identified as driving oncogenic events in subsets of papillary and medullary thyroid cancers (PTC and MTC), but targeted therapy for RET-driven cancers is currently clinically unavailable. Some mulit-kinase inhibitors, such as sunitinib and vandetanib, which have shown efficacy against other neoplastic diseases, are being evaluated in clinical trials for thyroid cancer therapy. However, the anti-VEGFR activities of these mulit-kinase inhibitors have been considered to lead cardiotoxicity in some patients. Moreover, Ret mutation-associated resistance have been reported by some RET inhibitors in preclinical data. The “in silico model” was applied to design the specific RET target compounds through mapping the pharmacophore of RET ATP-binding pocket. Some novel scaffold compounds which fit the pharmacophore model were selected form ITRI library, and their anti-RET activities were evaluated by kinase assay. The in vitro anti-cell proliferation activities of the compounds to the TT cells (MTC specific cells) were demonstrated by MTT assay. From the screening of ITRI library, ITRI-305 showed the impressive anti-RET (IC50 ∼ 90 nM) and anti-cell proliferation (IC50 at low micro molar) activities and the activities are compatible to those of sunitinib and vandetanib. ITRI-305 also shows good solubility and favorable oral PK profiles. The xenograft study of TT cells with ITRI-305 is proceeding. In conclusion, a novel scaffold RET inhibitor, ITRI-305, with less potent VEGFR activity (anti-VEFGR IC50 ∼ 1 μM) is developed to overcome the cardiotoxicity and resistance problems which is caused by conventional RET inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 728.