Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors.

Catalytic Domain / drug effects Cell Line, Tumor Drug Discovery Humans Leukemia, Myeloid, Acute / drug therapy Molecular Docking Simulation Molecular Targeted Therapy Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy Protein Kinase Inhibitors / chemistry
PI5P4K autophagy cancer covalent inhibitor drug discovery kinase phosphoinositide

Journal

Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030

Informations de publication

Date de publication:
21 05 2020
Historique:
received: 13 05 2019
revised: 14 11 2019
accepted: 13 02 2020
pubmed: 5 3 2020
medline: 21 5 2021
entrez: 5 3 2020
Statut: ppublish

Résumé

The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here, we present the discovery and characterization of a pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.

Identifiants

DOI: 10.1016/j.chembiol.2020.02.003 PMID: 32130941 PMC: PMC7286548
pubmed: 32130941
pii: S2451-9456(20)30067-2
doi: 10.1016/j.chembiol.2020.02.003
pmc: PMC7286548
mid: NIHMS1568701
pii:
doi:

Substances chimiques

Protein Kinase Inhibitors 0
PIP4K2A protein, human EC 2.7.1.-
Phosphotransferases (Alcohol Group Acceptor) EC 2.7.1.-
PIP4K2C protein, human EC 2.7.1.149

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

525-537.e6

Subventions

Organisme : NCI NIH HHS
ID : R01 CA197329
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM041890
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197588
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA210184
Pays : United States

Informations de copyright

Copyright © 2020 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests J.A.M. is a member of the scientific advisory board (SAB) of 908 Devices. L.C.C. is a founder and member of the Board of Directors of Agios Pharmaceuticals and is a founder and receives research support from Petra Pharmaceuticals. These companies are developing novel therapies for cancer. N.S.G. is a founder, SAB member, and equity holder in Gatekeeper, Syros, Petra, C4, B2S, and Soltego. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield, and Sanofi. N.S.G., T.Z., and N.P.K. are inventors on a patent application covering chemical matter in this publication owned by the Dana-Farber Cancer Institute.

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Auteurs

Sindhu Carmen Sivakumaren (SC)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Hyeseok Shim (H)

Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.

Tinghu Zhang (T)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Fleur M Ferguson (FM)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Mark R Lundquist (MR)

Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.

Christopher M Browne (CM)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Hyuk-Soo Seo (HS)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Marcia N Paddock (MN)

Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.

Theresa D Manz (TD)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbruecken, Germany.

Baishan Jiang (B)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Ming-Feng Hao (MF)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Pranav Krishnan (P)

Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Diana G Wang (DG)

Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.

T Jonathan Yang (TJ)

Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.

Nicholas P Kwiatkowski (NP)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.

Scott B Ficarro (SB)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

James M Cunningham (JM)

Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Jarrod A Marto (JA)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Sirano Dhe-Paganon (S)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Lewis C Cantley (LC)

Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA. Electronic address: lcantley@med.cornell.edu.

Nathanael S Gray (NS)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nathanael_gray@dfci.harvard.edu.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Domaine catalytique › Targeting the PI5P4K Lipid Kinase Family in...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Targeting the PI5P4K Lipid Kinase Family in...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Targeting the PI5P4K Lipid Kinase Family in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Targeting the PI5P4K Lipid Kinase Family in...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Leucémies › Leucémie myéloïde › Leucémie aigüe myéloïde › Targeting the PI5P4K Lipid Kinase Family in...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de docking moléculaire › Targeting the PI5P4K Lipid Kinase Family in...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Thérapie moléculaire ciblée › Targeting the PI5P4K Lipid Kinase Family in...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Phosphotransferases (Alcohol Group Acceptor) › Targeting the PI5P4K Lipid Kinase Family in...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Leucémie lymphoïde › Leucémie-lymphome lymphoblastique à précurseurs B et T › Targeting the PI5P4K Lipid Kinase Family in...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Targeting the PI5P4K Lipid Kinase Family in...