Discovering potential stabilizers for KRAS22RT G-quadruplex DNA: an alternative next generation approach to treat pancreatic cancer.

ABSTRACT

KRAS is the signature gene responsible for the occurrence of pancreatic cancer, which is a complex, multifactorial and intractable lethal malignancy. Prevention and treatment of the ailment have always been a key motivation behind the search for new therapeutic drug molecules. G-quadruplexes are non-canonical guanine-rich secondary structures, commonly formed at eukaryotic telomeric ends, oncogenic promotors and G-rich regions of the DNA. These G-quadruplexes play a crucial role in the regulation of gene expression and maintenance of genome integrity, therefore, they are considered as emerging potential therapeutic drug targets. The present study is concerned with the discovery of a potential stabilizer for KRAS22RT G-quadruplex DNA, located in the NHE region of the promotor, while inhibiting the upregulation of KRAS proto-oncogene, as an alternative approach for the treatment of pancreatic cancer. Various chemical libraries have been virtually screened against the targeted G4 structure and 143 compounds showed promising results. However, molecular dynamic studies, ADME and toxicity analyses predicted that three compounds belonging to the class of tetra-substituted phenanthrolines (i.e., 7i, 7j and 7k) can not only effectively stabilize KRAS22RT G4 structure but also have least toxic effects in the in vivo system. Therefore, it is highly recommended to further investigate their effectiveness and efficacy through experimental analysis in laboratory.Communicated by Ramaswamy H. Sarma.