The RET (Rearranged during Transfection) gene encodes a widely-expressed transmembrane receptor tyrosine kinase that plays important roles in neuronal signaling. However, RET fusion genes resulting from chromosomal rearrangement lead to constitutive activation of the RET kinase. Such gain-of-function RET fusions have been identified as driver oncogenes in multiple tumor types, including about 1-2% of lung adenocarcinomas. The selective RET inhibitors pralsetinib and selpercatinib have demonstrated that such agents can have significant therapeutic value to treat patients with mutant RET-driven tumors. In our drug discovery efforts to develop selective RET inhibitors, we identified a pyrrolo[2,3-d]pyrimidine hit from a kinase inhibitor data-mining exercise. This presentation will discuss the optimization of this scaffold to address off-target liabilities, resulting in lead compound methyl (4-(4-amino-5-(5-amino-4-chloro-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicy-clo[2.2.2]octan-1-yl)carbamate (GNF4477), which has demonstrated potent and selective inhibition of RET kinase, and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. GNF4477 was well-tolerated at established efficacious doses, and the plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo.

Discovery of novel pyrrolo[2,3d]pyrimidine RET inhibitors as potential therapeutic agents for the treatment of lung adenocarcinoma

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.