Asciminib

ABL001 (Asciminib) is an allosteric inhibitor of ABL kinase, and binds the myristate pocket similar to previous generations of allosteric inhibitors such as GNF-2 and GNF-5. ABL001 is ~100-fold more potent than GNF-2, but retains exquisite selectivity for ABL kinase compared to other kinases and also outside the kinase family. This probe retains potency for inhibition of BCR-ABL even in the context of all catalytic site mutations including T315I. ABL001 is efficacious as a single agent for use in both cells and animal models, and is currently being explored in combinations with active site inhibitors such as nilotinib, imatinib, and dasatinib. It should provide a valuable tool to the field for the study of BCR-ABL in the context of CML.

Reviewer Probe testing: ABL001 has been tested in our lab in the ABL1 NanoBRET TE assay using tracer K4. It demonstrated an IC50 of 2nM in HEK293 cells. This is consistent with recommended concentrations of up to 250nM. 

NMR and X-Ray crystallography studies confirmed that ABL001 binds to a pocket on the BCR-ABL kinase domain that is normally occupied by the myristoylated N-terminus of ABL1. Upon fusion with BCR, this myristoylated N-terminus that serves to autoregulate ABL1 activity is lost. ABL001 functionally mimics the role of the myristoylated N-terminus by occupying its vacant binding site and restores the negative regulation of the kinase activity; GNF-2 displayed a profile analogous to ABL001 but is ~100-fold less potent. Reviewer recommended concentration: “up to 1000 nM”, based on “The ABL001 concentration range includes the concentration 10-fold above the KCL-22 anti-proliferative IC50 (10nM) and concentrations that are achievable clinically (100nM and 1000nM)".