Discovery and Development of Novel Ret Inhibitors for the Treatment of Pervasive Malignancies

Abstract

Targeted cancer therapeutics represent the advent of a new therapeutic age, brought forth by the small molecule tyrosine kinase inhibitor (TKI) imatinib (Gleevec®). Imatinib is able to cause complete and sustained remissions in patients with chronic myelogenous leukemia (CML) driven by the Abelson (ABL) kinase, which caused a massive paradigm shift in how cancer is treated. The following research has been completed to extend the principles of imatinib therapy to the rearranged during transfection (RET) kinase. The RET kinase is involved in driving the pathology of medullary thyroid cancer (MTC), papillary thyroid carcinoma (PTC), certain non-small cell lung cancers (NSCLC), chronic myelomonocytic leukemia (CMML), tamoxifen resistant breast cancer, and Spitz melanoma. A heavily diverse population of solid and liquid carcinomas are driven by the RET oncogene, and patients presenting with these cancers could significantly benefit from a RET inhibitor. Previous drug discovery campaigns identified RET activity after therapeutic development for an unrelated kinase, as the case with vandetanib (Calpresa®) and cabozantinib (Cometriq®). Both agents fail to achieve dominant activity on RET and are more active on the vascular endothelial growth factor receptor 2 (VEGFR2), yet still achieve efficacy in RET driven tumors. This likely results from interrupting the oncogene cooperation between RET and VEGFR2; VEGFR2 provides the nutrients through angiogenesis that RET requires to promote proliferation and survival. We hypothesized that an equipotent RET/VEGFR2 dual inhibitor could maximize inhibiting the cooperation between RET and VEGFR2 in RET driven cancers. The inhibitor should be developed to maintain activity on all known RET mutations for treatment durability. In that case, the RET oncogene, despite mutating, will always be inhibited. Through research efforts, Pz-1 was identified as a sub-nanomolar, equipotent inhibitor of both RET (IC₅₀<0.001 µM) and VEGFR2 (IC₅₀<0.001 µM). Pz-1 was found active on every known, clinically relevant RET mutant tested at an IC₅₀≤0.001 µM. Through RET-driven xenograft models, Pz-1 was found active at an oral dose as low as 0.3 mg/kg/day.