Friday, April 26, 2024
4/26/2024
Project Summary Human cancers that contain the rearranged-during-transfection (RET) oncogene respond poorly to immune checkpoint inhibitors, but have high response rates to the potent and reasonably selective RET protein tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib. While selpercatinib and pralsetinib can inhibit RET V804M/L gatekeeper mutants, which are resistant to all other publicly known RET TKIs, the RET G810C/R/S solvent-front mutations have been identified as the major on-target resistant mechanisms to both selpercatinib and pralsetinib. We recently found that TKIs containing alkynyl nicotinamide scaffold were more drug-like than did the corresponding alkynyl benzamides. Through our collaboration, we identified several nicotinamide-based lead compounds that potently inhibit RET, its gatekeeper, solvent front, and roof mutants with selectivity against VEGFR2 and are orally available. These are highly desirable properties for a next-generation RET inhibitor. The long-term goal of this collaborative project is to further characterize the novel nicotinamide-based RET TKIs in order to develop a best-in-class, next-generation potent and selective RET inhibitor that can be used to treat acquired selpercatinib- and pralsetinib-resistant patients in addition to use as the first-line drug for RET-altered cancers. In this project, we will select the best lead compounds through multi-parametric characterization and structure-activity relationship optimization (Specific Aim 1); establish the absorption, distribution, metabolism, excretion, and toxicity (ADMET)-pharmacokinetic (PK) profile and PK/pharmacodynamic (PK/PD) relationship of selected compounds (Specific Aim 2); and evaluate PD biomarkers of kinase inhibition and anti-tumor efficacy of down-selected RET inhibitors in subcutaneous and intracranial tumors derived from engineered and human cancer cell lines, in lung tumors of transgenic mice, and in RET-altered cancer patient-derived xenografts (PDXs) (Specific Aim 3). Through this collaborative, novel multi-parametric selection and optimization effort that incorporates both in vitro and in vivo properties, we expect to obtain one or more potent and selective RET TKIs that are effective on selpercatinib- and pralsetinib-resistant RET mutants and are orally bioavailable with intracranial activity for further clinical development. This will facilitate the effort to increase the duration of tumor response to treatment towards the goal of turning a currently incurable malignancy into a manageable chronic condition, and ultimately a cure.
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