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

J Med Chem. 2018 Sep 27;61(18):8120-8135. doi: 10.1021/acs.jmedchem.8b01040.

Joseph Schoepfer ¹, Wolfgang Jahnke ¹, Giuliano Berellini, Silvia Buonamici, Simona Cotesta ¹, Sandra W Cowan-Jacob ¹, Stephanie Dodd ², Peter Drueckes ¹, Doriano Fabbro, Tobias Gabriel ¹, Jean-Marc Groell ¹, Robert M Grotzfeld ¹, A Quamrul Hassan, Chrystèle Henry ¹, Varsha Iyer, Darryl Jones ¹, Franco Lombardo, Alice Loo ², Paul W Manley ¹, Xavier Pellé ¹, Gabriele Rummel ¹, Bahaa Salem ¹, Markus Warmuth, Andrew A Wylie, Thomas Zoller ¹, Andreas L Marzinzik ¹, Pascal Furet ¹

Affiliations

1 Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland.
2 Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue , Cambridge , Massachusetts 02139 , United States.

PMID: 30137981 DOI: 10.1021/acs.jmedchem.8b01040

Abstract

Chronic myelogenous leukemia (CML) arises from the constitutive activity of the BCR-ABL1 oncoprotein. Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site have transformed CML into a chronic manageable disease. However, some patients develop drug resistance due to ATP-site mutations impeding drug binding. We describe the discovery of asciminib (ABL001), the first allosteric BCR-ABL1 inhibitor to reach the clinic. Asciminib binds to the myristate pocket of BCR-ABL1 and maintains activity against TKI-resistant ATP-site mutations. Although resistance can emerge due to myristate-site mutations, these are sensitive to ATP-competitive inhibitors so that combinations of asciminib with ATP-competitive TKIs suppress the emergence of resistance. Fragment-based screening using NMR and X-ray yielded ligands for the myristate pocket. An NMR-based conformational assay guided the transformation of these inactive ligands into ABL1 inhibitors. Further structure-based optimization for potency, physicochemical, pharmacokinetic, and drug-like properties, culminated in asciminib, which is currently undergoing clinical studies in CML patients.

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