What question did this study set out to answer?

Identify and optimize a selective allosteric inhibitor targeting the BCR-ABL1 myristate pocket to overcome resistance to standard ATP-competitive tyrosine kinase inhibitors.

August 23, 2018Journal of Medicinal ChemistryOpen Access

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1

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Authors

JSJoseph SchoepferNovartis (Switzerland)WJWolfgang JahnkeNovartis (Switzerland)GBGiuliano BerelliniAlkermes (United States)

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Overview

Preclinical study demonstrates targeted allosteric inhibition of BCR-ABL1 via the myristate pocket in leukemia models, highlighting a new strategy to overcome drug resistance mutations.

Key Points

Identify and optimize a selective allosteric inhibitor targeting the BCR-ABL1 myristate pocket to overcome resistance to standard ATP-competitive tyrosine kinase inhibitors.
Screened fragment libraries using nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to identify binders of the BCR-ABL1 myristate pocket.
Guided chemical optimization through an NMR-based conformational assay and structure-based design to enhance potency, physicochemical properties, and pharmacokinetics.
Discovered asciminib (ABL001), a clinical-stage allosteric inhibitor that binds specifically to the myristate pocket and retains activity against ATP-site resistant BCR-ABL1 mutants.
Showed that combination therapy with asciminib and ATP-competitive inhibitors suppresses the emergence of mutually exclusive resistance mutations in both binding pockets.

Cite This Study

Schoepfer et al. (2018) studied this question.

synapsesocial.com/papers/69dbcd29498b35d3e6a3d2a1 https://doi.org/10.1021/acs.jmedchem.8b01040

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August 23, 2018Journal of Medicinal ChemistryOpen Access

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1

View Full Paper

Ask AI

Bookmark

Authors

JSJoseph SchoepferNovartis (Switzerland)WJWolfgang JahnkeNovartis (Switzerland)GBGiuliano BerelliniAlkermes (United States)

Discussion

Member takes

Overview

Preclinical study demonstrates targeted allosteric inhibition of BCR-ABL1 via the myristate pocket in leukemia models, highlighting a new strategy to overcome drug resistance mutations.

Key Points

Identify and optimize a selective allosteric inhibitor targeting the BCR-ABL1 myristate pocket to overcome resistance to standard ATP-competitive tyrosine kinase inhibitors.
Screened fragment libraries using nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to identify binders of the BCR-ABL1 myristate pocket.
Guided chemical optimization through an NMR-based conformational assay and structure-based design to enhance potency, physicochemical properties, and pharmacokinetics.
Discovered asciminib (ABL001), a clinical-stage allosteric inhibitor that binds specifically to the myristate pocket and retains activity against ATP-site resistant BCR-ABL1 mutants.
Showed that combination therapy with asciminib and ATP-competitive inhibitors suppresses the emergence of mutually exclusive resistance mutations in both binding pockets.

Cite This Study

Schoepfer et al. (2018) studied this question.

synapsesocial.com/papers/69dbcd29498b35d3e6a3d2a1 https://doi.org/10.1021/acs.jmedchem.8b01040

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