Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1 PMID: 30137981

ADC Targets in Oncology

2026-04-10

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

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.