Asciminib (ABL001)

Catalog No.S8555 Batch:S855501

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Technical Data

Formula

C20H18ClF2N5O3
Molecular Weight 449.84 CAS No. 1492952-76-7
Solubility (25°C)* In vitro DMSO 89 mg/mL (197.84 mM)
Ethanol 89 mg/mL (197.84 mM)
Water Insoluble
In vivo (Add solvents to the product individually and in order)
5%DMSO 40%PEG300 5%Tween80 50%ddH2O
4.5mg/ml
5% DMSO 95% Corn oil
0.55mg/ml
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description Asciminib (ABL001) is a potent and selective allosteric ABL1 inhibitor with dissociation constant (Kd) of 0.5-0.8 nM and selectivity to the myristoyl pocket of ABL1.
Targets
Abl1 [1]
(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[1]. 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[2]. 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[1]. NMR and biophysical studies confirm that ABL001 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. 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[3].
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[1]. 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 T1/2term are 1.1 and 3.7 h after a single i.v. dose at 1 mg/kg. In Rat, theT1/2term 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)[3].

Protocol (from reference)

Cell Assay:

[3]
  • Cell lines

    KCL-22 cells

  • Concentrations

    0-250 nM

  • Incubation Time

    1 h

  • Method

    KCL-22 cells are treated across a range of concentrations of ABL001, nilotinib or dasatinib for 1 hour. Cells are harvested, protein lysates generated and analyzed with Western Blots.
Animal Study:

[3]
  • Animal Models

    Subcutaneous KCL-22 CML xenograft model (athymic nude mice, 6-8 weeks old)

  • Dosages

    7.5, 15 and 30 mg/kg

  • Administration

    p.o or i.v

Customer Product Validation

Data from [Data independently produced by , , Leukemia, 2017, 31(11):2376-2387]

Selleck's Asciminib (ABL001) has been cited by 11 publications

Effect of asciminib and vitamin K2 on Abelson tyrosine-kinase-inhibitor-resistant chronic myelogenous leukemia cells [ BMC Cancer, 2023, 23(1):827] PubMed: 37670241
Effect of asciminib and vitamin K2 on Abelson tyrosine-kinase-inhibitor-resistant chronic myelogenous leukemia cells [ BMC Cancer, 2023, 23(1):827] PubMed: 37670241
Reengineering Ponatinib to Minimize Cardiovascular Toxicity [ Cancer Res, 2022, 82-15:2777-2791] PubMed: 35763671
Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma [ Int J Mol Sci, 2022, 23(24)16162] PubMed: 36555805
Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma [ Int. J. Mol. Sci, 2022, 23(24), 16162] PubMed: None
PI3-kinase inhibition as a strategy to suppress the leukemic stem cell niche in Ph+ chronic myeloid leukemia [ Am J Cancer Res, 2021, 11(12):6042-6059] PubMed: 35018241
Patient-derived xenografts and in vitro model show rationale for imatinib mesylate repurposing in HEY1-NCoA2-driven mesenchymal chondrosarcoma [ Lab Invest, 2021, 10.1038/s41374-021-00704-4] PubMed: 34837064
Crizotinib acts as ABL1 inhibitor combining ATP-binding with allosteric inhibition and is active against native BCR-ABL1 and its resistance and compound mutants BCR-ABL1T315I and BCR-ABL1T315I-E255K [ Ann Hematol, 2021, 10.1007/s00277-020-04357-z] PubMed: 34110462
c-Abl kinase regulates neutrophil extracellular trap formation, inflammation, and tissue damage in severe acute pancreatitis. [ J Leukoc Biol, 2019, 106(2):455-466] PubMed: 30861207
KDM3A histone demethylase functions as an essential factor for activation of JAK2-STAT3 signaling pathway [ Proc Natl Acad Sci U S A, 2018, 115(46):11766-11771] PubMed: 30377265

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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