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Asciminib (ABL001) Bcr-Abl inhibitor

Name: Asciminib (ABL001)
Brand: Selleck Chemicals
SKU: S8555
Availability: InStock
Rating: 5 (15 reviews)

Catalog No.S8555 Purity:99.88%

A potent and selective allosteric ABL1 inhibitor, Asciminib (ABL001) has a dissociation constant (Kd) of 0.5-0.8 nM and selectivity to the myristoyl pocket of ABL1.

Chemical Structure

Molecular Weight: 449.84

Purity & Quality Control

Batch: Purity: 99.88%

99.88

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Signaling Pathway

Bcr-Abl Signaling Pathway

Mechanism of Action

Targets

Abl1 ^[1]
(Cell-free assay)

0.45 nM

In vitro
In vitro	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].
Cell Research	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 Asciminib (ABL001) for 1 hour. After treatment with this compound, cells are harvested, protein lysates generated and analyzed with Western Blots.

In Vivo
In vivo	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].
Animal Research	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

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT06409936	Not yet recruiting	CML Chronic Phase\|Chronic Myeloid Leukemia Chronic Phase\|Chronic Myeloid Leukemia BCR/ABL-Positive\|Chronic Myeloid Leukemia	Gruppo Italiano Malattie EMatologiche dell''Adulto\|Fundacion Espanola para la Curacion de la Leucemia Mieloide Cronica	September 2024	Phase 2
NCT06092879	Recruiting	Chronic Myeloid Leukemia	Novartis Pharmaceuticals\|Novartis	March 6 2024	--
NCT06211153	Completed	Chronic Myeloid Leukemia With T315I Mutation	Novartis Pharmaceuticals\|Novartis	December 31 2021	--
NCT04795427	Active not recruiting	Leukemia Chronic Myelogenous	Novartis Pharmaceuticals\|Novartis	December 6 2021	Phase 2
NCT04492033	Active not recruiting	P1b: Advanced Solid Tumors\|P2: Biliary Tract Cancer	Handok Inc.\|Compass Therapeutics\|ABL Bio Inc.	June 22 2020	Phase 1\|Phase 2

References

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

Chemical Information

Molecular Weight	449.84	Formula	C₂₀H₁₈ClF₂N₅O₃
CAS No.	1492952-76-7	SDF	--
Synonyms	N/A
Smiles	C1CN(CC1O)C2=C(C=C(C=N2)C(=O)NC3=CC=C(C=C3)OC(F)(F)Cl)C4=CC=NN4

Storage and Stability

Storage (From the date of receipt)	3 years-20°Cpowder	Storage of Stock Solutions Aliquot the stock solutions to avoid repeated freeze-thaw cycles	1 year-80°Cin solvent
			1 month-20°Cin solvent

In vitro
Batch:

DMSO : 89 mg/mL ( (197.84 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 89 mg/mL

Water : Insoluble

Molecular Weight Calculator

In vivo Batch: Add solvents to the product individually and in order.				In vivo Formulation Calculator
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O Validated by Selleck labs. Should you need adjustments to this formulation, contact our sales team for custom testing.	4.500mg/ml (10.00mM)
	5% DMSO 1 95% Corn oil Validated by Selleck labs. Should you need adjustments to this formulation, contact our sales team for custom testing.	0.550mg/ml (1.22mM)
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

Preparing Stock Solutions

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
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Dilution Calculator Molecular Weight Calculator

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

Dosage: mg/kg Average weight of animals: g Dosing volume per animal:μL Number of animals:

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

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

Tel: +1-832-582-8158 Ext:3
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