Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo

ACS Chemical Biology
Mark C WeirThomas E Smithgall

Abstract

Acute myelogenous leukemia (AML) is the most common hematologic malignancy in adults and is often associated with constitutive tyrosine kinase signaling. These pathways involve the nonreceptor tyrosine kinases Fes, Syk, and the three Src-family kinases expressed in myeloid cells (Fgr, Hck, and Lyn). In this study, we report remarkable anti-AML efficacy of an N-phenylbenzamide kinase inhibitor, TL02-59. This compound potently suppressed the proliferation of bone marrow samples from 20 of 26 AML patients, with a striking correlation between inhibitor sensitivity and expression levels of the myeloid Src family kinases Fgr, Hck, and Lyn. No correlation was observed with Flt3 expression or mutational status, with the four most sensitive patient samples being wild-type for Flt3. Kinome-wide target specificity profiling coupled with in vitro kinase assays demonstrated a narrow overall target specificity profile for TL02-59, with picomolar potency against the myeloid Src-family member Fgr. In a mouse xenograft model of AML, oral administration of TL02-59 for 3 weeks at 10 mg/kg completely eliminated leukemic cells from the spleen and peripheral blood while significantly reducing bone marrow engraftment. These results identify Fgr as a ...Continue Reading

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Citations

Apr 25, 2019·BMC Genomics·Alexander G FooteSusan L Thibeault
May 30, 2019·Proceedings of the National Academy of Sciences of the United States of America·Koichiro AbeMartin Hrabe de Angelis
Jul 28, 2020·Cancers·Edwige VoissetPaulo de Sepulveda
Jul 25, 2019·International Journal of Molecular Sciences·Solène FernandezPierre-Yves Dumas
Dec 19, 2019·Frontiers in Chemistry·Heather R DormanThomas E Smithgall
Jan 29, 2021·Molecular and Cellular Biochemistry·Mona G El-SisiHala O El-Mesallamy
Jan 13, 2021·Cancers·Kalpana K BhanumathyVincenzo Giambra
Jun 10, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Jennifer K TrittmannLeif D Nelin
Nov 14, 2021·Cell Death Discovery·Amitava MukherjeeJoel S Greenberger
Dec 14, 2021·Journal of Molecular Biology·Ivette PerezT M Iverson

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