5KPL

Glycogen Synthase Kinase 3 beta Complexed with BRD0705

Summary for 5KPL

• Entry DOI: 10.2210/pdb5kpl/pdb
• Related: 5KPK 5KPM
• Descriptor: Glycogen synthase kinase-3 beta, (4~{S})-4-ethyl-7,7-dimethyl-4-phenyl-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one (3 entities in total)
• Functional Keywords: protein kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P49841
• Total number of polymer chains: 2
• Total formula weight: 95001.80

Authors

Lakshminarasimhan, D.,White, A.,Nadupalli, A.,Suto, R.K. (deposition date: 2016-07-04, release date: 2018-03-14, Last modification date: 2024-10-23)

Primary citation

Wagner, F.F.,Benajiba, L.,Campbell, A.J.,Weiwer, M.,Sacher, J.R.,Gale, J.P.,Ross, L.,Puissant, A.,Alexe, G.,Conway, A.,Back, M.,Pikman, Y.,Galinsky, I.,DeAngelo, D.J.,Stone, R.M.,Kaya, T.,Shi, X.,Robers, M.B.,Machleidt, T.,Wilkinson, J.,Hermine, O.,Kung, A.,Stein, A.J.,Lakshminarasimhan, D.,Hemann, M.T.,Scolnick, E.,Zhang, Y.L.,Pan, J.Q.,Stegmaier, K.,Holson, E.B.
Exploiting an Asp-Glu "switch" in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia.
Sci Transl Med, 10:-, 2018

PubMed 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 Asp→Glu "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.

PubMed: 29515000
DOI: 10.1126/scitranslmed.aam8460

Experimental method

X-RAY DIFFRACTION (2.6 Å)