Discovery of 4-aminopyrimidine analogs as highly potent dual P70S6K/Akt inhibitors.

Animals Antineoplastic Agents / chemistry Area Under Curve Dogs Drug Discovery Female Half-Life Haplorhini Mammary Neoplasms, Animal / drug therapy Mice Molecular Docking Simulation Molecular Structure Proto-Oncogene Proteins c-akt / antagonists & inhibitors Pyrimidines / chemistry Rats Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors Structure-Activity Relationship TOR Serine-Threonine Kinases / genetics
4-Aminopyrimidines Akt Breast cancer p70S6K

Journal

Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377

Informations de publication

Date de publication:
15 10 2021
Historique:
received: 15 07 2021
revised: 16 08 2021
accepted: 29 08 2021
pubmed: 6 9 2021
medline: 11 1 2022
entrez: 5 9 2021
Statut: ppublish

Résumé

Activation of the PI3K/Akt/mTOR kinase pathway is associated with human cancers. A dual p70S6K/Akt inhibitor is sufficient to inhibit strong tumor growth and to block negative impact of the compensatory Akt feedback loop activation. A scaffold docking strategy based on an existing quinazoline carboxamide series identified 4-aminopyrimidine analog 6, which showed a single-digit nanomolar and a micromolar potencies in p70S6K and Akt enzymatic assays. SAR optimization improved Akt enzymatic and p70S6K cellular potencies, reduced hERG liability, and ultimately discovered the promising candidate 37, which exhibited with a single digit nanomolar value in both p70S6K and Akt biochemical assays, and hERG activities (IC

Identifiants

DOI: 10.1016/j.bmcl.2021.128352 PMID: 34481987
pubmed: 34481987
pii: S0960-894X(21)00579-5
doi: 10.1016/j.bmcl.2021.128352
pii:
doi:

Substances chimiques

Antineoplastic Agents 0
Pyrimidines 0
Proto-Oncogene Proteins c-akt EC 2.7.11.1
Ribosomal Protein S6 Kinases, 70-kDa EC 2.7.11.1
TOR Serine-Threonine Kinases EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

128352

Commentaires et corrections

Type : ErratumIn

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Auteurs

Yufang Xiao (Y)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA. Electronic address: Yufang.Xiao@emdserono.com.

Bayard R Huck (BR)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA. Electronic address: Bayard.Huck@emdserono.com.

Ruoxi Lan (R)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Lizbeth DeSelm (L)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Xiaoling Chen (X)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Hui Qiu (H)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Constantin Neagu (C)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Theresa Johnson (T)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Igor Mochalkin (I)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Anna Gardberg (A)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Xuliang Jiang (X)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Hui Tian (H)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Vikram Dutt (V)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Dusica Santos (D)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Jared Head (J)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Jennifer Jackson (J)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Sakeena Syed (S)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Jing Lin (J)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Erik Wilker (E)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Jianguo Ma (J)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Anderson Clark (A)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Andreas Machl (A)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Donald Bankston (D)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Christopher C V Jones (CCV)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Andreas Goutopoulos (A)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

Brian Sherer (B)

EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Aire sous la courbe › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Carnivora › Pinnipedia › Canidae › Chiens › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Phénomènes physiques › Temps › Période › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Maladies de l'animal › Tumeurs mammaires de l'animal › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de docking moléculaire › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Phénomènes chimiques › Structure moléculaire › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-akt › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Ribosomal Protein S6 Kinases › Ribosomal Protein S6 Kinases, 70-kDa › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Discovery of 4-aminopyrimidine analogs as...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Discovery of 4-aminopyrimidine analogs as...