Exploring Secondary Metabolites from Extremophilic Streptomyces for RET Inhibition in Non-Small Cell Lung Cancer

Lung cancer is the second most prevalent cancer globally, with significant mortality rates among both smokers and nonsmokers. Targeting RET gene, which has been linked to the onset of non-small cell lung cancer (NSCLC) cases, offers a novel therapeutic avenue. Vandetanib, a tyrosine kinase inhibitor (TKI) of the RET gene, has several adverse effects, including skin toxicity, EGFR-induced diarrhea and VEGFR-related hypertension. Thus, we sought to identify promising candidates for RET inhibition employing a combination of in silico techniques. In this regard, we intend to investigate secondary metabolites from Streptomyces species, which are renowned for their therapeutic potential. A total of 3383 compounds produced by the Streptomyces species under extreme conditions were identified utilizing the antiSMASH database. Through molecular docking, the compounds were screened against the RET protein, identifying 43 compounds with better docking scores than vandetanib (-8.7 kcal/mol). Subsequent ADMET analysis and machine learning validation using KDEEP, GNINA and RF scoring functions highlighted Esmeraldin B as a leading candidate. Esmeraldin B demonstrated superior binding affinity and interaction profiles, establishing five hydrogen bonds and hydrophobic interactions. Further, the scaffold analysis revealed that Esmeraldin B's phenazine moiety contributes to its potent antitumor properties. Collectively, these findings suggest that Esmeraldin B holds promise as a more effective and potentially safer alternative to vandetanib for RET-positive NSCLC. However, extensive in vitro and in vivo studies are required to confirm its therapeutic potential and to ensure safety for clinical and therapeutic applications.