Asciminib (ABL001) - 98%, high purity , Tyrosine-protein kinase ABL inhibitor, CAS No.1492952-76-7, Tyrosine-protein kinase ABL inhibitor

Item Number

A414054

• Synonyms: asciminib|1492952-76-7|ABL-001|ABL001|ABL001-NX|Asciminib free base|NVP-ABL001|Example 9|Asciminib [USAN]|L1F3R18W77|UNII-L1F3R18W77|(R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide|1492952-76-7 (free ba
• Specifications & Purity: Moligand™, ≥98%
• Biochemical and Physiological Mechanisms: Asciminib (ABL001) is a potent and selective allosteric ABL1 inhibitor with dissociation constant (Kd) of\u20090.5-0.8\u2009nM and selectivity to the myristoyl pocket of ABL1.
• Storage Temp: Store at -20°C
• Shipped In: Ice chest + Ice pads
• Grade: Moligand™
• Action Type: ALLOSTERIC MODULATOR, INHIBITOR
• Mechanism of action: Tyrosine-protein kinase ABL inhibitor

Product Description

Information

Asciminib (ABL001) is a potent and selective allostericABL1inhibitor with dissociation constant (Kd) of 0.5-0.8 nM and selectivity to the myristoyl pocket of ABL1.

Targets

Abl1 (Cell-free assay) 0.45 nM

In vitro

ABL001 is a potent, selective BCR-ABL inhibitor that maintains activity across most mutations, including T315I, with a distinct, allosteric mechanism of action. ABL001 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. It 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. ABL001 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. NMR and biophysical studies confirm that ABL001 binds potently (dissociation constant (Kd)\u2009=\u20090.5-0.8\u2009nM) and selectively to the myristoyl pocket of ABL1 and induces the inactive C-terminal helix conformation. ABL001 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, ABL001 has high selectivity.

In vivo

In the KCL-22 mouse xenograft model, ABL001 displays potent anti-tumor activity with complete tumor regression observed and a clear dose-dependent correlation with pSTAT5 inhibition. ABL001 has moderate oral absorption, volume of distribution and half-life across all species. It 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 of ABL001, The CL (clearance) are 12, 16 and 6 mL/min/kg in mice, rats and dogs after a sigle 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 of ABL001 in mouse and rat are 35% and 27% respectively when dosed at 30 mg/kg p.o. While in dogs the oral BA of ABL001 is 111% (15 mg/kg, p.o).

Cell Research(from reference)

Cell lines：KCL-22 cells 

Concentrations：0-250 nM 

Incubation Time：1\u2009h