high-throughput-expression-purification-human-solute-carriers-for

High-Throughput Expression and Purification of Human Solute Carriers for Structural and Biochemical Studies

Solute carriers (SLCs) are membrane transporters that import and export a range of endogenous and exogenous substrates, including ions, nutrients, ...

University of Oxford

Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of , an analogue of the previously reported ALK2 inhibitor . Although highly selective for ALK2 over the TGF-βR1 receptor ALK5,  is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue  with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.

Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.

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

Eleanor P. Williams

Centre for Medicines Discovery,
Nuffield Department of Medicine,
Centre for Medicines Discovery, Nuffield Department of Medicine

University of Oxford

High-Throughput Expression and Purification of Human Solute Carriers for Structural and Biochemical Studies

Eleanor P. Williams

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University of Oxford

High-Throughput Expression and Purification of Human Solute Carriers for Structural and Biochemical Studies

Centre for Medicines Discovery,
Nuffield Department of Medicine,
Centre for Medicines Discovery, Nuffield Department of Medicine