Escaping from Flatland: 3D Carborane-Based Bioisosteres of Erlotinib as Potential Anticancer Agents

Phenyl rings are present in nearly 45% of approved small-molecule drugs; however, their flat, aromatic nature can lead to poor solubility, metabolic instability, and limited target selectivity. Carboranes, as three-dimensional boron-rich bioisosteres, may offer a promising alternative to address these limitations. Here, we report the design, synthesis, and biological characterization of novel carborane-based analogs of erlotinib, exploring 3D bioisosterism to enhance anticancer activity. All the carborane-based analogs displayed better <i>in vitro</i> biological behavior than the parent compound, with the <i>para</i>-derivatives (<b>13</b>) and (<b>17</b>) emerging as promising leads, showing 2.5 to >12-fold greater cytotoxicity than erlotinib and up to ∼7-fold selectivities for glioblastoma over astrocytes. Compound (<b>17</b>) moderately inhibited both wild-type EGFR (IC₅ ₀ = 9.23 μM) and the drug-resistant EGFR_T790M mutant (IC₅ ₀ = 7.19 μM). Molecular docking and dynamics simulations predicted binding within the ATP catalytic site, displaying a hinge-binding mode characteristic of EGFR inhibitors. Mechanistic studies revealed apoptosis as the predominant cell death pathway. <i>In vivo</i>, compound (<b>17</b>) showed excellent acute oral safety (LD₅ ₀ > 2000 mg/kg in mice) with no alterations in biochemical blood parameters. Ames testing indicated no mutagenic potential. <i>In silico</i> ADMET profiling predicted high intestinal absorption, absence of P-gp interaction, weak hERG inhibition, and no carcinogenicity, with only compounds (<b>16</b>) and (<b>17</b>) predicted to cross the blood-brain barrier. Chemical stability assays demonstrated that all compounds, except (<b>18</b>), were stable for 24 h under physiologically relevant pH conditions (2.0, 7.0, and 8.6). Overall, these findings position compound (<b>17</b>) as a promising lead for glioblastoma tumors. Despite modest biochemical potency, its strong cellular efficacy suggests additional mechanisms of action beyond direct EGFR inhibition. Future efforts will focus on kinome-wide profiling and transcriptomic analyses to elucidate its broader target spectrum and optimize this scaffold for clinical translation.