Identification and Evaluation in silico and in vitro of Small Molecules in the KRas4B‐PDEδ Molecular Complex in Pancreatic Cancer

Abstract

Pancreatic cancer (PDAC) is the most lethal of all cancer types, characterized by an average survival of 6 months and a five‐years survival rate of less than 5%. To increase the survival rate of pancreatic cancer patients is necessary to search for improved tumor markers for an earliest diagnosis and new molecular targets for drug development. In most cases, PDAC is initiated by the mutant of GTPase KRas4B, which has been shown to drive pancreatic neoplasia. Furthermore, it has been demonstrated that nearly 95% of PDAC shown mutational activated KRas4B. Certainly, KRas4B protein has been used as a principal target in anticancer drugs development. Therefore, the identification of new organic molecules that recognize the KRas4B‐PDEδ molecular complex is of great interest for its stabilization for avoiding the activation of KRas4B in the cytoplasmic membrane. Thus, the objective of this work is to identify and evaluate new small molecules that stabilize the KRas4B‐PDEδ complex by using docking techniques. First, we constructed a homology model of KRas4B‐PDEδ complex and this revealed a set of exposed non‐conserved residues at the interface, which are considered an important target for ligand identification. Then, we carried out a docking simulation between the extensive database of drug‐like compounds from ENAMINE and the non‐conserved site at the Kras4B‐PDEδ model using a previous reported protocol. The in vitro evaluation of fourteen compounds with high scores from docking showed a significant specific effect in three of them on the viability of pancreatic cancer cell line MIAPaCa‐2 but not in the pancreatic cell line hTERT‐HPNE used as a control. Interestingly, the compounds decreased Ras‐GTP concentration in the cell line MIAPaCa‐2 in more than 50%, indicating a reduced activity. In conclusion, our results open the possibility to develop drugs against to PDCA; however, we need to perform more experiments in order to establish the specific mechanism of action of the compounds developed in this work.Support or Funding InformationThis work was sponsored by the CONACYT and ISSSTE project number: 002.2015 ISSSTE