• Joseph Schoepfer, Wolfgang Jahnke, Giuliano Berellini, Silvia Buonamici, Simona Cotesta, Sandra W Cowan-Jacob, Stephanie Dodd, Peter Drueckes, Doriano Fabbro, Tobias Gabriel, Jean-Marc Groell, Robert M Grotzfeld, A Quamrul Hassan, Chrystèle Henry, Varsha Iyer, Darryl Jones, Franco Lombardo, Alice Loo, Paul W Manley, Xavier Pellé, Gabriele Rummel, Bahaa Salem, Markus Warmuth, Andrew A Wylie, Thomas Zoller, Andreas L Marzinzik, and Pascal Furet.
• Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland.
• J. Med. Chem. 2018 Sep 27; 61 (18): 8120-8135.

AbstractChronic 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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