Evidence map›Paper›PMID 36812145›Full record

ArticleACS chemical neuroscience2023

Elucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors.

Brenda Amaral, Andrew Capacci, Trip Anderson, Ceren Tezer, Bekim Bajrami, Mukesh Lulla, Brian Lucas, Jayanth V Chodaparambil, Douglas Marcotte, P Rajesh Kumar and 13 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in ACS chemical neuroscience, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
1.7field-weighted citation impact, top 16% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed, 11 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors at 1 institution in 1 country.

Brenda AmaralDepartments of Research, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Andrew CapacciDepartments of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Trip AndersonDepartments of Research, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Ceren TezerDepartments of Research, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Bekim BajramiDepartments of Chemical Biology and Proteomics, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Mukesh LullaDepartments of Drug Metabolism and Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Brian LucasDepartments of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Jayanth V ChodaparambilDepartments of Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Douglas MarcotteDepartments of Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
P Rajesh KumarDepartments of Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Paramasivam MuruganDepartments of Bioassays, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Kerri SpilkerDepartments of Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Mike CullivanDepartments of Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Ti WangDepartments of Bioassays, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Anton C PetersonDepartments of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Istvan EnyedyDepartments of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Bin MaDepartments of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
TeYu ChenDepartments of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Zain YousafDepartments of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Michael CalhounDepartments of Research, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Olga GolonzhkaDepartments of Research, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Gregory M DillonDepartments of Research, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.ORCID 0000-0002-3673-284X
Samir KoiralaDepartments of Research, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Biogen (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development of small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition of both GSK3 paralogs, leading to activation of the Wnt/β-catenin pathway and potential for aberrant cell proliferation. Development of GSK3α or GSK3β paralog-selective inhibitors that could offer an improved safety profile has been reported but further advancement has been hampered by the lack of structural information for GSK3α. Here we report for the first time the crystal structure for GSK3α, both in apo form and bound to a paralog-selective inhibitor. Taking advantage of this new structural information, we describe the design and in vitro testing of novel compounds with up to ∼37-fold selectivity for GSK3α over GSK3β with favorable drug-like properties. Furthermore, using chemoproteomics, we confirm that acute inhibition of GSK3α can lower tau phosphorylation at disease-relevant sites in vivo, with a high degree of selectivity over GSK3β and other kinases. Altogether, our studies advance prior efforts to develop GSK3 inhibitors by describing GSK3α structure and novel GSK3α inhibitors with improved selectivity, potency, and activity in disease-relevant systems.

Indexed as

Glycogen Synthase Kinase 3Protein Serine-Threonine KinasesCell ProliferationGlycogen Synthase Kinase 3 betaPhosphorylationGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaProtein Serine-Threonine KinasesAlzheimer’sGSK3αGSK3βkinase inhibitortauβ-catenin

Identifiers

PMID36812145
PMCPMC10020971
OpenAlexW4321488198

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.