Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma.
Activin Receptors, Type I
/ antagonists & inhibitors
Animals
Antineoplastic Agents
/ chemical synthesis
Diffuse Intrinsic Pontine Glioma
/ drug therapy
Drug Discovery
Female
HEK293 Cells
Humans
Male
Mice, SCID
Molecular Structure
Protein Kinase Inhibitors
/ chemical synthesis
Rats, Sprague-Dawley
Structure-Activity Relationship
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
10 09 2020
10 09 2020
Historique:
pubmed:
14
8
2020
medline:
19
12
2020
entrez:
14
8
2020
Statut:
ppublish
Résumé
There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound
Identifiants
pubmed: 32787083
doi: 10.1021/acs.jmedchem.0c01199
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
Activin Receptors, Type I
EC 2.7.11.30
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10061-10085Subventions
Organisme : Wellcome Trust
ID : 106169/ZZ14/Z
Pays : United Kingdom