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

Autor:	Schoepfer J; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Jahnke W; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Berellini G, Buonamici S, Cotesta S; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Cowan-Jacob SW; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Dodd S; Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue , Cambridge , Massachusetts 02139 , United States., Drueckes P; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Fabbro D, Gabriel T; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Groell JM; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Grotzfeld RM; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Hassan AQ, Henry C; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Iyer V, Jones D; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Lombardo F, Loo A; Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue , Cambridge , Massachusetts 02139 , United States., Manley PW; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Pellé X; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Rummel G; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Salem B; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Warmuth M, Wylie AA, Zoller T; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Marzinzik AL; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland., Furet P; Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 Sep 27; Vol. 61 (18), pp. 8120-8135. Date of Electronic Publication: 2018 Sep 07.
DOI:	10.1021/acs.jmedchem.8b01040
Abstrakt:	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.
Databáze:	MEDLINE
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