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Formula | C20H18ClF2N5O3 |
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Molecular Weight | 449.84 | CAS No. | 1492952-76-7 | |
Solubility (25°C)* | In vitro | DMSO | 90 mg/mL (200.07 mM) | |
Ethanol | 30 mg/mL (66.69 mM) | |||
Water | Insoluble | |||
* <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.) |
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. | ||
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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]. |
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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]. |
Cell Assay: |
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Animal Study: |
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Data from [Data independently produced by , , Leukemia, 2017, 31(11):2376-2387]
ABL1-mediated phosphorylation promotes FOXM1-related tumorigenicity by Increasing FOXM1 stability [ Cell Death Differ, 2024, 10.1038/s41418-024-01339-w] | PubMed: 39060421 |
The molecular basis of Abelson kinase regulation by its αI-helix [ Elife, 2024, 12RP92324] | PubMed: 38588001 |
Asciminib Maintains Antibody-Dependent Cellular Cytotoxicity against Leukemic Blasts [ Cancers (Basel), 2024, 16(7)1288] | PubMed: 38610966 |
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 |
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