Using novel heterocyclic compounds as small molecule inhibitors against flt3 receptor tyrosine kinase associated with molecular docking

سال انتشار: 1396
نوع سند: مقاله کنفرانسی
زبان: انگلیسی
مشاهده: 477

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شناسه ملی سند علمی:

NASTARANCANSER03_048

تاریخ نمایه سازی: 7 اسفند 1396

چکیده مقاله:

Acute Myelogenous Leukemia (AML) is a hematopoietic malignancy that is characterized by aberrant proliferation of myeloid progenitor cells, coupled to a partial block in cellular differentiation. AMLaccounts for approximately 25% of all leukemias in adults and constitutes the most frequent form of leukemia. The most important cause of AML is a mutation in protein kinases such as FLT3, KIT,NRas, KRas. FLT3 (FMS-Like Tyrosine kinase) mutation occur in about 30% of these patients. Internal tandem duplication (ITD) in the juxtamembrane domain renders the kinase domain constitutivelyactive. The most recent specified strategy for cancer therapy involved using Small Molecule Inhibitors (SMIs) against mutated receptor including FLT3-ITD. A set of 12 novel heterocyclic compounds composed of a common core (ethyl (2E)-3-[(5-bromo-6-methylpyrimidin-4-yl)amino]-2-cyanoprop-2- enoate) structure and different substituents used in this study. Two murine cell lines of FD-FLT3-WTand FD-FLT3-ITD dependent to human FLT3 receptor were used for doing cellular examinations. Cytotoxicity evaluation was performed using Resazurin reagent for both cell lines in the presence of various growth factors (FLT3 ligand and GM-CSF) for the FD-FLT3-WT line to achieve IC50. The interactions of the inhibitor compounds and the homology models FLT3 were evaluated by moleculardocking method using GOLD and Accelrys Discovery Studio software. Among 12 recruited compounds, three compounds show the powerful effect on both cell lines, however, some compounds were eliminated from the investigation based on their physical properties. Considering FD-FLT3-ITD, compounds A1, A9 and A12 could result in the IC50 values of 130,140 and 7 μM, respectively. Although, these heterocyclic rings affected much more potently on FD-FLT3-WT cell line. Moreover, the docking result revealed that compound 12 was docked with lowest energy level among all especially in active homology models involved 1PKG and 2GQG. In both experimental and in silico studies, compounds A1, A9 and especially A12 were considered as the best compounds of this category due to their specific activity and potent receptor-ligand interactions

نویسندگان

Shokouh Shahrokhi Sabzevar

Department Of Medical Genetics, Faculty Of Medicine, Mashhad Medical University Of Sciences, Mashhad, Iran

Mohammad Hossein Tanipour

Department Of Medical Biochemistry, School Of Medicine, Mashhad University Of Medical Sciences, Mashhad, Iran

Mohammad Saadatmandzadeh

Faculty Of Sciences, Department Of Chemistry, Ferdowsi University Of Mashhad, Mashhad, Iran

Baratali Mashkani

Department Of Medical Biochemistry, School Of Medicine, Mashhad University Of Medical Sciences, Mashhad, Iran