2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.12A.01 Preclinical Characterization of a Potent, Selective, Brain-Penetrant Inhibitor of Osimertinib-Resistant EGFR Variants

EP.12A.01 Preclinical Characterization of a Potent, Selective, Brain-Penetrant Inhibitor of Osimertinib-Resistant EGFR Variants

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The study focused on the preclinical characterization of STC-1282, a potent and selective inhibitor developed for treating osimertinib-resistant EGFR variants, specifically targeting conditions where patients develop the C797S mutation. STC-1282 is designed to maintain potency against EGFR variants without affecting the wild-type EGFR (EGFR WT), showing similar selectivity as osimertinib against Ex19 Del and L858R cell lines while retaining effectiveness even when the C797S resistance mutation is present.<br /><br />The inhibitor demonstrates high efficacy in suppressing phosphorylated EGFR (pEGFR) signaling in mutant EGFR cell lines, with a single- to double-digit nanomolar potency. It shows less potency in cell lines with EGFR WT and primary human keratinocytes, expressed in micromolar ranges, thus sparing normal skin cells from adverse effects typically associated with EGFR inhibitors.<br /><br />Importantly, STC-1282 is also brain-penetrant, evidenced by its strong anti-tumor activity and survival benefits in an intracranial PC-9-luc tumor model. The median survival rates with STC-1282 at increasing dosages (1 mg/kg, 3 mg/kg, and 10 mg/kg) were notably higher than other treatments like brigatinib, gefitinib, and osimertinib, showcasing the potential long-term benefits of STC-1282 for patients with osimertinib resistance.<br /><br />The research involved collaboration with Syngene and Pharmaron for in vitro data, and WuXi AppTec's oncology group for in vivo studies. Data analysis and visualization were conducted using GraphPad Prism, and BioRender was used for creating schematic representations. The study was funded by Schrödinger Inc., with most authors being employees of the company, indicating a vested interest in the development and success of STC-1282.

Asset Subtitle

Katherine Amberg-Johnson

Meta Tag

Speaker Katherine Amberg-Johnson

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

STC-1282

EGFR inhibitor

osimertinib resistance

C797S mutation

brain-penetrant

phosphorylated EGFR

intracranial tumor model

Syngene collaboration

Pharmaron collaboration

Schrödinger Inc.