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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 LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.

Original publication

DOI

10.1021/acs.jmedchem.0c01199

Type

Journal article

Journal

J Med Chem

Publication Date

10/09/2020

Volume

63

Pages

10061 - 10085

Keywords

Activin Receptors, Type I, Animals, Antineoplastic Agents, Diffuse Intrinsic Pontine Glioma, Drug Discovery, Female, HEK293 Cells, Humans, Male, Mice, SCID, Molecular Structure, Protein Kinase Inhibitors, Rats, Sprague-Dawley, Structure-Activity Relationship