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Purity: ≥98%
Asciminib (formerly known as ABL-001; ABL001; trade name Scemblix) is a potent and selective allosteric inhibitor of BCR-ABL1 approved in Oct 2021 to treat Philadelphia chromosome-positive CML (chronic myeloid leukemia) with disease that meets certain criteria. It selectively inhibits BCR-ABL1 by binding to its myristoyl pocket, with a dissociation constant (Kd) of 0.5-0.8 nM. With an IC50 of 0.25 nM, asciminib also prevents the proliferation of Ba/F3 cells. Patients with CML and acute lymphoblastic leukemia with the Philadelphia chromosome (Ph+) are participating in clinical trials for it. Asciminib attaches to ABL1's myristoyl pocket and causes the kinase conformation to become inactive, in contrast to catalytic-site ABL1 kinase inhibitors. Genetic barcoding studies have revealed pre-existing clonal populations with no shared resistance between asciminib and the catalytic inhibitor nilotinib. Asciminib and 2nd-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations. Thus, when combined with nilotinib in an in vivo model of chronic myeloid leukemia in mice, asciminib inhibits the development of resistant disease.
| Targets |
Abl1 (IC50 = 2.8 nM); TrkA (IC50 = 6 nM); Abl1 (IC50 = 2.8 nM); TrkB (IC50 = 9 nM); Tie-2 (IC50 = 22 nM); Aurora B (IC50 = 98 nM)
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| ln Vitro |
ABL001 is a potent, selective BCR-ABL inhibitor with a unique, allosteric mode of action that remains active against the majority of mutations, including T315I[1]. By binding to a regulatory site that wild-type ABL normally possesses a myristoyl group occupying, ABL001 inhibits ABL kinase activity in a different way than catalytic site inhibitors[2]. The myristoylated N-terminus of ABL1 typically resides in a pocket on the BCR-ABL kinase domain, which is where it binds. This myristoylated N-terminus is responsible for autoregulating ABL1 activity; it is lost upon fusion with BCR. By taking up its empty binding site, ABL001 functionally imitates the myristoylated N-terminus'sfunctionand reinstates the kinase activity's negative regulation. BCR-ABL-negative cell lines were unaffected at concentrations 1000 times higher than ABL001, which specifically inhibits the growth of Ph+ ALL and chronic myelogenous leukemia (CML) cells at potencies ranging from 1 to 10 nM[1]. ABL001 selectively and potently binds to the myristoyl pocket of ABL1 and induces the inactive C-terminal helix conformation, as confirmed by NMR and biophysical studies (dissociation constant (Kd) = 0.5-0.8 nM). ABL001 is inactive against G-protein-coupled receptors, ion channels, nuclear receptors, and transporters, among more than 60 kinases, including SRC. ABL001 is therefore highly selective[3].
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| ln Vivo |
ABL001 exhibits strong anti-tumor activity in the KCL-22 mouse xenograft model, as evidenced by total tumor regression and a pronounced dose-dependent relationship with pSTAT5 inhibition[1]. All species have a moderate half-life, volume of distribution, and oral absorption of ABL001. For patients with chronic myelogenous leukemia who have received a lot of pretreatment, it has been well tolerated as a single agent and has been shown to induce clinical anti-tumor activity. Regarding the pharmacokinetics, pharmacodynamics, and efficacy of ABL001, the CL (clearance) in mice, rats, and dogs following a single intravenous dose of 1 mg/kg, 2 mg/kg, and 1 mg/kg, respectively, are 12, 16, and 6 mL/min/kg. The T1/2term for a single intravenous dose of 1 mg/kg in mice and dogs are 1.1 and 3.7 hours, respectively. Rats have a T1/2term of 2.7 hours following a single intravenous dose of 2 mg/kg. Oral bioavailability of ABL001 at 30 mg/kg p.o. in rats and mice is 35% and 27%, respectively. On the other hand, ABL001's oral BA in dogs is 111% (15 mg/kg, p.o)[3].
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| Enzyme Assay |
Asciminib, having a dissociation constant (Kd) of 0.5-0.8 nM and selectivity to the myristoyl pocket of ABL1, is a strong and selective allosteric inhibitor of BCR-ABL1.
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| Cell Assay |
For 48 hours, Ba/F3 cells are exposed to asciminib at a range of concentrations (0–10,000 nM). The Britelite luciferase detection assay is used to quantify the proliferation of cells.
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| Animal Protocol |
Mice: Asciminib efficacy is measured using FACS monitoring of the percentage of CD45+ cells per live cell in blood samples obtained at different times following dosing with either 7.5 mg/kg BID (group 2) or 30 mg/kg BID (group 3) asciminib for three weeks in three patient-derived ALL systemic xenograft models (ALL-7015, AL-7119, and AL-7155).
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| References |
| Molecular Formula |
C20H18CLF2N5O3
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| Molecular Weight |
449.84
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| Exact Mass |
449.11
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| Elemental Analysis |
C, 53.40; H, 4.03; Cl, 7.88; F, 8.45; N, 15.57; O, 10.67
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| CAS # |
1492952-76-7
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| Related CAS # |
Asciminib hydrochloride;2119669-71-3
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| Appearance |
Solid powder
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| SMILES |
C1CN(C[C@@H]1O)C2=C(C=C(C=N2)C(=O)NC3=CC=C(C=C3)OC(F)(F)Cl)C4=CC=NN4
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| InChi Key |
VOVZXURTCKPRDQ-CQSZACIVSA-N
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| InChi Code |
InChI=1S/C20H18ClF2N5O3/c21-20(22,23)31-15-3-1-13(2-4-15)26-19(30)12-9-16(17-5-7-25-27-17)18(24-10-12)28-8-6-14(29)11-28/h1-5,7,9-10,14,29H,6,8,11H2,(H,25,27)(H,26,30)/t14-/m1/s1
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| Chemical Name |
N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.56 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.56 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2230 mL | 11.1151 mL | 22.2301 mL | |
| 5 mM | 0.4446 mL | 2.2230 mL | 4.4460 mL | |
| 10 mM | 0.2223 mL | 1.1115 mL | 2.2230 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04795427 | Active Recruiting |
Other: best available treatment Drug: asciminib |
Leukemia, Chronic Myelogenous | Novartis Pharmaceuticals | December 6, 2021 | Phase 2 |
| NCT04948333 | Active Recruiting |
Drug: ABL001 40mg BID Drug: ABL001 80mg QD |
Chronic Myelogenous Leukemia | Novartis Pharmaceuticals | October 13, 2021 | Phase 3 |
| NCT03906292 | Active Recruiting |
Drug: Imatinib Drug: Asciminib |
Chronic Myeloid Leukemia | University of Jena | August 19, 2019 | Phase 2 |
| NCT03106779 | Active Recruiting |
Drug: Bosutinib Drug: Asciminib |
Chronic Myelogenous Leukemia | Novartis Pharmaceuticals | October 26, 2017 | Phase 3 |
| NCT05943522 | Recruiting | Other: Asciminib | Chronic Myeloid Leukemia | Novartis Pharmaceuticals | July 19, 2023 |
ABL001 is an allosteric inhibitor of BCR–ABL1 that selectively inhibits growth of BCR–ABL1-driven cells.Nature.2017 Mar 30;543(7647):733-737. |
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ABL001 has a resistance profile that is distinct from catalytic-site BCR–ABL1 inhibitors.Nature.2017 Mar 30;543(7647):733-737. |
The non-overlapping resistance profiles of ABL001 and nilotinib enable durable tumour eradication when used in combination.Nature.2017 Mar 30;543(7647):733-737. |
Clonal evolution of resistance mutations in a patient treated with ABL001 after previous dasatinib treatment.Nature.2017 Mar 30;543(7647):733-737. |
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