In Silico Evaluation of a Promising Key Intermediate Thieno [2,3-d] Pyrimidine Derivative with Expected JAK2 Kinase Inhibitory Activity

Elshaymaa Elmongy,Hanan Henidi

doi:10.3390/m1352

Elshaymaa Elmongy, Hanan Henidi

Open Access

https://doi.org/10.3390/m1352

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Abstract

This work describes the synthesis and the cytotoxic evaluation of thiophene and thienopyrimidine derivatives. The investigated compound was subjected to target prediction that indicated its high affinity to kinases and to Janus kinase 2 (JAK2) specifically. Molecular docking screening was performed on three different JAK2 proteins downloaded from the Protein Data Bank (PDB: 5AEP, 4C62 and 3ZMM). In vitro kinase inhibitory activity was evaluated and then compound cytotoxicity was performed on three different cancerous cell lines (HT-29, HepG-2, and MCF-7). Marked cytotoxic activity of the thienopyrimidine derivative against the HepG-2 cell line was demonstrated, reflected by its IC50 value of 8.001 ± 0.0445 μM, which is better than that of the reference standard (IC50 13.91 ± 2.170 μM). Pharmacokinetic studies revealed good well permeability and GI absorption with no violations against Lipinski’s rule.

Highlights

IntroductionCancer is the global second leading cause of disease-related mortality and morbidity [1]
This work describes the cytotoxic evaluation of a thienopyrimidine derivative along with its in silico modeling studies and pharmacokinetics assessment
Target prediction revealed the high affinity to kinases, Janus kinase 2 (JAK2)

Summary

Introduction

Cancer is the global second leading cause of disease-related mortality and morbidity [1]. Thienopyrimidines, with a heterocyclic core derivatized from pyrimidine and resembling purines, are of unique importance as scaffolds for the preparation of a variety of biologically active compounds as enzyme inhibitors, including kinases [4,5], poly (ADPribose) polymerase (PARP) inhibitors [6], and as anticancer agents against some tumor cell lines [7–11], in addition to their antioxidant activity [12–14]. They are an interesting target for protein kinases (PKs), which are enzymes known to regulate proteinbiological activity, as they are responsible for protein phosphorylation that is involved in cell cycle proliferation, in addition to regulating cell progression and division [15–17]. Mutations in JAK2 have been implicated in many myeloproliferative and myelofibrosis disorders [19]

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