Asciminib (ABL001)

Catalog No.S8555

For research use only.

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.

Asciminib (ABL001) Chemical Structure

CAS No. 1492952-76-7

Selleck's Asciminib (ABL001) has been cited by 5 Publications

1 Customer Review

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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 Research:

[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.

  • (Only for Reference)
Animal Research:

[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
  • (Only for Reference)

Solubility (25°C)

In vitro

DMSO 89 mg/mL
(197.84 mM)
Ethanol '89 mg/mL

* 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.

Chemical Information

Molecular Weight 449.84
Formula

C20H18ClF2N5O3

CAS No. 1492952-76-7
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles C1CN(CC1O)C2=C(C=C(C=N2)C(=O)NC3=CC=C(C=C3)OC(F)(F)Cl)C4=CC=NN4

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04795427 Not yet recruiting Drug: asciminib|Other: best available treatment Leukemia Chronic Myelogenous Novartis Pharmaceuticals|Novartis March 30 2022 Phase 2
NCT04492033 Recruiting Drug: ABL001|Drug: Paclitaxel|Drug: Irinotecan P1b: Advanced Solid Tumors|P2: Biliary Tract Cancer Handok Inc.|ABL Bio Inc. June 22 2020 Phase 1|Phase 2
NCT03605277 Completed Drug: Asciminib Renal Impairment Novartis Pharmaceuticals|Novartis November 16 2018 Phase 1
NCT03578367 Recruiting Drug: Asciminib add-on|Drug: Imatinib|Drug: Nilotinib CML|Chronic Myelogenous Leukemia|Leukemia Myeloid Chronic|Hematologic Diseases Novartis Pharmaceuticals|Novartis November 22 2018 Phase 2

(data from https://clinicaltrials.gov, updated on 2021-09-06)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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