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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species

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Published on: February 27, 2018

Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease.

Amanda Van de Poël¹, Leticia Toledo-Sherman², Perla Breccia¹

¹Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K.

Journal of Medicinal Chemistry

|March 30, 2021

Summary

New brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors show promise for Huntington's disease (HD) treatment. Optimized compounds achieve high ATM potency and selectivity over Vps34, improving therapeutic potential.

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Area of Science:

Medicinal Chemistry
Neuroscience
Molecular Biology

Background:

Huntington's disease (HD) is a neurodegenerative disorder linked to impaired autophagy.
Ataxia telangiectasia-mutated (ATM) kinase inhibitors are being explored as potential HD therapeutics.
Previous inhibitors lacked selectivity, inhibiting vacuolar protein sorting 34 (Vps34) kinase involved in autophagy.

Purpose of the Study:

To optimize ATM kinase inhibitors for selectivity over Vps34.
To develop novel therapeutics for Huntington's disease with improved properties.

Main Methods:

Utilized X-ray crystal structures of a Vps34-ATM protein chimera.
Mutated the Vps34 ATP-binding site to mimic ATM kinase.
Synthesized and evaluated novel morpholino-pyridone and morpholino-pyrimidinone compounds.

Main Results:

Achieved successful selectivity optimization of ATM over Vps34.
Developed compounds with high ATM potency and good oral bioavailability.
Resulting compounds exhibited lower molecular weight, reduced lipophilicity, and higher aqueous solubility compared to prior inhibitors.

Conclusions:

Optimized ATM kinase inhibitors demonstrate enhanced selectivity and drug-like properties.
These novel compounds represent promising therapeutic candidates for Huntington's disease.
Targeting ATM with selective inhibitors offers a viable strategy for neurodegenerative disease treatment.