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

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

  • Sci Transl Med. 2018 Mar 7;10(431):eaam8460. doi: 10.1126/scitranslmed.aam8460.
Florence F Wagner 1,  Lina Benajiba 2 3 4 5,  Arthur J Campbell 6,  Michel Weïwer 6,  Joshua R Sacher 6,  Jennifer P Gale 6,  Linda Ross 3 4,  Alexandre Puissant 3 4 7,  Gabriela Alexe 2 3 4 8,  Amy Conway 3 4,  Morgan Back 3 4,  Yana Pikman 2 3 4,  Ilene Galinsky 9,  Daniel J DeAngelo 9,  Richard M Stone 9,  Taner Kaya 6,  Xi Shi 6,  Matthew B Robers 10,  Thomas Machleidt 10,  Jennifer Wilkinson 10,  Olivier Hermine 11 12,  Andrew Kung 13,  Adam J Stein 14,  Damodharan Lakshminarasimhan 15,  Michael T Hemann 16,  Edward Scolnick 6,  Yan-Ling Zhang 6,  Jen Q Pan 6,  Kimberly Stegmaier 17 3 4,  Edward B Holson 6
Affiliations

Affiliations

  • 1 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.
  • 2 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
  • 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 4 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 5 INSERM U1163 and CNRS 8254, Imagine Institute, Université Paris Saclay, 91190 Paris, France.
  • 6 Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
  • 7 INSERM U944, Institute of Hematology, St. Louis Hospital, 75010 Paris, France.
  • 8 Bioinformatics Graduate Program, Boston University, Boston, MA 02215, USA.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 10 Promega Corporation, 2800 Woods Hollow Road, Madison, WI 53711, USA.
  • 11 INSERM U1163 and CNRS 8254, Imagine Institute, Université Sorbonne Paris Cité, Paris, France.
  • 12 Department of Hematology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, 75006 Paris, France.
  • 13 Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
  • 14 Cayman Chemical Co., Ann Arbor, MI 48108, USA.
  • 15 Xtal BioStructures Inc., Natick, MA 01760, USA.
  • 16 Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 17 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. fwagner@broadinstitute.org kimberly_stegmaier@dfci.harvard.edu.
PMID: 29515000 DOI: 10.1126/scitranslmed.aam8460
Abstract

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 Asp133→Glu196 "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.

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