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Asciminib (ABL001) Bcr-Abl inhibitor

Cat.No.S8555

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) Bcr-Abl inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 449.84

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Chemical Information, Storage & Stability

Molecular Weight 449.84 Formula

C20H18ClF2N5O3

 Storage (From the date of receipt)
CAS No. 1492952-76-7 -- Storage of Stock Solutions

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

Solubility

In vitro
Batch:

DMSO : 89 mg/mL (197.84 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 89 mg/mL

Water : Insoluble

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Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
Abl1 [1]
(Cell-free assay)
0.45 nM
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].
In vivo

In the KCL-22 mouse xenograft model, Asciminib (ABL001) displays potent anti-tumor activity with complete tumor regression observed and a clear dose-dependent correlation with pSTAT5 inhibition[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 T1/2term are 1.1 and 3.7 h after a single i.v. dose at 1 mg/kg. In Rat, the T1/2term 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].
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
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

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