Targeting <scp>TUBG1</scp> in <scp>RB1</scp> ‐negative tumors

The disruption of microtubule dynamics serves as a pivotal strategy for eliminating tumor cells, despite its accompanying toxicities affecting non-tumor cells. This study investigates the potential of selectively targeting γ-tubulin1 (TUBG1) as a therapeutic strategy in cancer treatment. By elucidating the TUBG1-E2F1-retinoblastoma protein (RB1) network, we introduce a novel compound, 4-(6-((3-Methoxyphenyl)amino)pyrimidin-4-yl)-N,N-dimethylbenzenamine, (L12). L12 treatment enhanced RB1 expression and selectively targeted cells with impaired RB1 signaling, while reduced E2F1 expression attenuated its cytotoxicity. Furthermore, L12-mediated cytotoxicity depends on an E2F1-mediated upregulation of procaspase 3 expression, highlighting the role of E2F1 in the apoptotic response. Unlike traditional tubulin-targeting agents, L12's specificity for tumor cells lies in its inhibitory effects on TUBG1, without affecting the second human isoform of TUBGs, TUBG2. Despite its interaction with specific kinases, the concentrations required for antitumor effects are 100-fold lower than those influencing kinase activities. Subsequent investigations underscore L12's reduced neuronal axonal toxicity compared to vincristine. Lastly, L12 demonstrates promising results in inhibiting tumor growth in xenografted small cell lung cancer models, demonstrating potential specificity toward tumor cells while minimizing adverse effects on healthy tissues. This research emphasizes the potential of TUBG1 inhibitors as a promising advancement in personalized chemotherapy approaches and their potential as a groundbreaking treatment for various cancers.