Asciminib (ABL001)

Asciminib (ABL001) is a potent, selective BCR-ABL inhibitor that maintains activity across most mutations, including T315I, with a distinct, allosteric mechanism of action^[1]. It binds at a regulatory site typically occupied by a myristoyl group in wild-type ABL and inhibits ABL kinase activity through a mechanism distinct from catalytic site inhibitors^[2]. This compound 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. It selectively inhibits the growth of chronic myelogenous leukemia (CML) and Ph+ ALL cells with potencies ranging from 1-10 nM range while BCR-ABL-negative cell lines remained unaffected at concentrations 1000-fold higher^[1]. NMR and biophysical studies confirm that it binds potently (dissociation constant (Kd) = 0.5-0.8 nM) and selectively to the myristoyl pocket of ABL1 and induces the inactive C-terminal helix conformation. This compound lacks activity against more than 60 kinases, including SRC and is similarly inactive against G-protein-coupled receptors, ion channels, nuclear receptors and transporters. Thus, it has high selectivity^[3].

Asciminib (ABL001) displays potent anti-tumor activity with complete tumor regression observed and a clear dose-dependent correlation with pSTAT5 inhibition in the KCL-22 mouse xenograft model^[1]. It has moderate oral absorption, volume of distribution and half-life across all species. This compound as a single agent induces clinical anti-tumour activity and is well tolerated to date in a heavily pre-treated subgroup of patients with chronic myelogenous leukemia. As for the pharmacokinetics, pharmacodynamics and efficacy, the CL (clearance) are 12, 16 and 6 mL/min/kg in mice, rats and dogs after a single iv dose of 1mg/kg, 2mg/kg and 1mg/kg, respectively. In mouse and dog, the T_1/2term are 1.1 and 3.7 h after a single i.v. dose at 1 mg/kg. In Rat, theT_1/2term is 2.7 h after a single i.v. dose at 2 mg/kg. The oral bioavailability in mouse and rat are 35% and 27% respectively when dosed at 30 mg/kg p.o. While in dogs the oral BA is 111% (15 mg/kg, p.o)^[3].

KCL-22 cells are treated across a range of concentrations of Asciminib (ABL001) for 1 hour. After treatment with this compound, cells are harvested, protein lysates generated and analyzed with Western Blots.

• http://www.bloodjournal.org/content/124/21/398?sso-checked=true
• http://clincancerres.aacrjournals.org/content/23/1_Supplement/IA01
• https://www.nature.com/articles/nature21702