DRUG DESIGNING FOR TARGETING FLT3 RECEPTOTTYROSINE KINASE FOR LEUKEMIA DISEASE

Scholarly Research Journal for Interdisciplinary Studies, Online ISSN 2278-8808, SJIF 2016 = 6.17, www.srjis.com UGC Approved Sr. No.49366, NOV-DEC 2017, VOL- 4/37

DRUG DESIGNING FOR TARGETING FLT3 RECEPTOTTYROSINE KINASE FOR LEUKEMIA DISEASE ShailjaSingla & Nikunaj Bhardwaj Noida International University, Greater Noida

More than 30% of acute myeloid leukemia (AML) patients possess activating mutations in the receptor tyrosine kinase FMS-like tyrosine kinase 3 or FLT3. A small-molecule inhibitor of FLT3 (tyrosine kinase) that is currently in clinical trials appears promising for the treatment of AML. Here, we report the co-crystal structure of the kinase domain of FLT3 in complex with RTK. FLT3 with quizartinib bound adopts an “Abl-like” inactive conformation with the activation loop stabilized in the “DFG-out” orientation and folded back onto the kinase domain. This conformation is similar to that observed for the uncomplexed intracellular domain of FLT3 as well as for related receptor tyrosine kinases, except for a localized induced fit in the activation loop.The co-crystal structure reveals the interactions between RTK and the active site of FLT3 that are key for achieving its high potency against both wild-type FLT3 as well as aFLT3 variant observed. Keywords:myeloid leukemia (AML), tyrosine kinase 3, co-crystal structure Scholarly Research Journal's is licensed Based on a work at www.srjis.com

INTRODUTION Leukemia is a form of cancer that affects blood-forming tissues such as bone marrow andis associated with uncontrolled growth of white blood cells (Leukocytes).Continuous production of leukemic cells overwhelm the bone marrow, enter the bloodstream, and eventually invade other parts of the body such as the lymph nodes, spleen, liver, central and peripheral nervous systems.Incidence of leukemia ranges between 10-18 per 100,000persons per year worldwide with a little male dominance, while the mortality rate is 5-9per 100,000 per year. Current drugs used in leukemia treatment are Quinoxaline AG1296, Indolinones SU5416 and SU11248, Indolocarbazoles PKC412. Other drugs that are used less offen include Cytarabine, Daunorubicin, Doxorubicin, Idarubicin, Mitoxantrone, Vincristi, Sunitinib, Dasatinib, Nilotinib, Axitinib, Imatinib, Carbozanitinib, Sorafenib, Pazopanib, Tandutinib MLN-518, Vatalanib, Gemtuzumab, CyclophosphamideAnd Cytarabine MARKERS IN LEUKEMIA OR TARGET OF CURRENT DRUGS AND FLT3 RECEPTOR PROTEIN KINASE

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DRUG DESIGNING FOR TARGETING FLT3 RECEPTOTTYROSINE KINASE FOR LEUKEMIA DISEASE

Published on Apr 16, 2018

Scholarly Research Journal"s

More than 30% of acute myeloid leukemia (AML) patients possess activating mutations in the receptor tyrosine kinase FMS-like tyrosine kinase 3 or FLT3. A small-molecule inhibitor of FLT3 (tyrosine kinase) that is currently in clinical trials appears promising for the treatment of AML. Here, we report the co-crystal structure of the kinase domain of FLT3 in complex with RTK. FLT3 with quizartinib bound adopts an “Abl-like” inactive conformation with the activation loop stabilized in the “DFG-out” orientation and folded back onto the kinase domain. This conformation is similar to that observed for the uncomplexed intracellular domain of FLT3 as well as for related receptor tyrosine kinases, except for a localized induced fit in the activation loop.The co-crystal structure reveals the interactions between RTK and the active site of FLT3 that are key for achieving its high potency against both wild-type FLT3 as well as aFLT3 variant observed. Keywords:myeloid leukemia (AML), tyrosine kinas