Exploring Secondary
Metabolites from Extremophilic Streptomyces for RET Inhibition in Non-Small Cell
Lung Cancer
Gupta Nistha, Manoj Angelina, Jayakumar Gayathri and Veerappapillai Shanthi
Res. J. Chem. Environ.; Vol. 29(11); 9-17;
doi: https://doi.org/10.25303/2911rjce09017; (2025)
Abstract
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.
