Exploiting an Asp-Glu "switch" in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia.

Autor:	Wagner FF; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. fwagner@broadinstitute.org kimberly_stegmaier@dfci.harvard.edu., Benajiba L; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.; INSERM U1163 and CNRS 8254, Imagine Institute, Université Paris Saclay, 91190 Paris, France., Campbell AJ; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA., Weïwer M; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA., Sacher JR; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA., Gale JP; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA., Ross L; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA., Puissant A; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.; INSERM U944, Institute of Hematology, St. Louis Hospital, 75010 Paris, France., Alexe G; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.; Bioinformatics Graduate Program, Boston University, Boston, MA 02215, USA., Conway A; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA., Back M; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA., Pikman Y; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA., Galinsky I; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., DeAngelo DJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Stone RM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Kaya T; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA., Shi X; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA., Robers MB; Promega Corporation, 2800 Woods Hollow Road, Madison, WI 53711, USA., Machleidt T; Promega Corporation, 2800 Woods Hollow Road, Madison, WI 53711, USA., Wilkinson J; Promega Corporation, 2800 Woods Hollow Road, Madison, WI 53711, USA., Hermine O; INSERM U1163 and CNRS 8254, Imagine Institute, Université Sorbonne Paris Cité, Paris, France.; Department of Hematology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, 75006 Paris, France., Kung A; Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA., Stein AJ; Cayman Chemical Co., Ann Arbor, MI 48108, USA., Lakshminarasimhan D; Xtal BioStructures Inc., Natick, MA 01760, USA., Hemann MT; Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02142, USA., Scolnick E; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA., Zhang YL; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA., Pan JQ; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA., Stegmaier K; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. fwagner@broadinstitute.org kimberly_stegmaier@dfci.harvard.edu.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA., Holson EB; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2018 Mar 07; Vol. 10 (431).
DOI:	10.1126/scitranslmed.aam8460
Abstrakt:	Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of β-catenin are associated with many cancers. Knockdown of GSK3α or GSK3β individually does not increase β-catenin and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, inadequate chemical tools exist. The design of selective adenosine triphosphate (ATP)-competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity and 100% similarity) in this binding domain. Taking advantage of an Asp 133 →Glu 196 "switch" in their kinase hinge, we present a rational design strategy toward the discovery of paralog-selective GSK3 inhibitors. These GSK3α- and GSK3β-selective inhibitors provide insights into GSK3 targeting in acute myeloid leukemia (AML), where GSK3α was identified as a therapeutic target using genetic approaches. The GSK3α-selective compound BRD0705 inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells, with no apparent effect on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies demonstrate feasibility of paralog-selective GSK3α inhibition, offering a promising therapeutic approach in AML. (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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