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Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.

Original publication

DOI

10.1038/s42003-019-0420-8

Type

Journal article

Journal

Commun Biol

Publication Date

2019

Volume

2

Keywords

CNS cancer, Paediatric cancer, Target validation, Activin Receptors, Type I, Administration, Oral, Animals, Antineoplastic Agents, Apoptosis, Brain Stem Neoplasms, Cell Line, Tumor, Cell Proliferation, Child, Diffuse Intrinsic Pontine Glioma, Drug Administration Schedule, Drug Evaluation, Preclinical, Female, Gene Expression, High-Throughput Screening Assays, Humans, Mice, Mice, SCID, Mutation, Protein Kinase Inhibitors, Pyrazoles, Pyridines, Pyrimidines, Survival Analysis, Xenograft Model Antitumor Assays