Structure-Activity Relationship Study of Covalent Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
12 Mar 2020
12 Mar 2020
Historique:
received:
30
08
2019
accepted:
03
11
2019
entrez:
19
3
2020
pubmed:
19
3
2020
medline:
19
3
2020
Statut:
epublish
Résumé
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are important molecular players in a variety of diseases, such as cancer. Currently available PI5P4K inhibitors are reversible small molecules, which may lack selectivity and sufficient cellular on-target activity. In this study, we present a new class of covalent pan-PI5P4K inhibitors with potent biochemical and cellular activity. Our designs are based on THZ-P1-2, a covalent PI5P4K inhibitor previously developed in our lab. Here, we report further structure-guided optimization and structure-activity relationship (SAR) study of this scaffold, resulting in compound
Identifiants
pubmed: 32184968
doi: 10.1021/acsmedchemlett.9b00402
pmc: PMC7074221
doi:
Types de publication
Journal Article
Langues
eng
Pagination
346-352Subventions
Organisme : NCI NIH HHS
ID : R01 CA197329
Pays : United States
Informations de copyright
Copyright © 2019 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare the following competing financial interest(s): 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. and T.Z. are inventors on a patent application covering chemical matter in this publication, owned by Dana-Farber Cancer Institute. L.C.C. is a founder and member of the Board of Directors (BOD) of Agios Pharmaceuticals and is a founder and receives research support from Petra Pharmaceuticals. These companies are developing novel therapies for cancer. J.A.M. serves on the SAB of 908 Devices.
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