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

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.