Asciminib

Protein target name:

BCR-ABL

Mechanism of action:

Allosteric Inhibitor

Recommended Concentration for use in cells:

~~up to 250 nM~~

Reviewer suggested Concentration for use in cells:

up to 1 uM

Probe Availability

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:76

Entrez gene ID:

UNIPROT ID:

P00519

Target alias:

Dmel_CG4032, 4674, ABL1, AblK, Ableson, Am ABL, C-abl, CG4032, D-Abl, D-abl, D-ash, DAbl, DROTKABL3, Dabl, Dash, Ddash/abl, Dmel\CG4032, Dsrc7

Probe Details

Chemical Probes Portal ID:

CPP2127

Probe alias:

ABL001, AY7

PubChem CID:

72165228

ChEMBL ID:

CHEMBL4208229

SMILES string:

O=C(C1=CC(C2=NNC=C2)=C(N3C[C@H](O)CC3)N=C1)NC4=CC=C(OC(F)(Cl)F)C=C4

InChi Key:

VOVZXURTCKPRDQ-CQSZACIVSA-N

Orthogonal probe:

GNF-5BafetinibImatinib

Physico-chemical properties

NMR:

1H-NMR (400 MHz, DMSOd6) δ ppm 1.65 - 1.76 (m, 1 H) 1.76 - 1.87 (m, 1 H) 2.93 (d, J = 11.73 Hz, 1 H) 3.19 - 3.29 (m, 2 H) 3.35 - 3.51 (m, 1 H) 4.10 - 4.25 (m, 1 H) 4.89 (br. s, 1 H) 6.41 (br. s, 1 H) 7.33 (d, J = 8.50 Hz, 2 H) 7.57/7.83 (br. s, 1 H) 7.90 (d, J = 8.50 Hz, 2 H) 8.07 (br. s, 1 H) 8.77 (br. s, 1 H) 10.23 (s, 1 H) 12.97/13.15 (br. s, 1 H);

13C-NMR (101 MHz, DMSO-d6) δ 32.95, 46.92, 57.42, 68.77, 105.96, 113.51, 117.31, 121.35, 121.74, 124.99 (t, J = 289.8 Hz), 128.33, 138.75, 144.72, 147.52, 149.18, 157.22, 164.17

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

0.5-0.8 nM

Potency assay:

ITC, conformational NMR assay

PDB ID for probe-target interaction (3D structure):

5MO4

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

ABL001 lacks activity against more than 60 kinases, including SRC. Inactive against G-protein-coupled receptors, ion channels, nuclear receptors and transporter

In cell validation

On target activity in cells

Potency in cells:

IC50

0.25 nM

Off target activity in cells

Probe Selectivity in Cell:

Cellular activity of ABL001was determined in 450 cancer cell lines from the Cancer Cell Line Encyclopedia proving that ABL001 is active against all BCR-ABL1 lines (IC50s 1-20 nM).

In vivo validation

Organism:

MouseRatDog

Dose:

1 (M), 2(R), 1(D) mg/Kg IV30 (M), 30 (R), 15 (D) 30 mg/Kg PO

Route of delivery:

OralIntravenous

Plasma half life:

1.1(M), 2.7(R), 3.7(D) h

Systemic clearance:

12 (M), 16 (R), 6 (D) mL/min/kg

Cmax:

8 (M), 2.7(R), 17 (D) uM

Tmax:

2 (M), 4 (R), 0.8 (D) h

Primary Reference

Reference (doi):

10.1038/nature21702 10.1182/blood.V124.21.398.398

Reference (PMID):

28329763

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

ABL001 (Asciminib) is an allosteric inhibitor of ABL kinase, and binds the myristate pocket similar to previous generations of allosteric inhibitors such as GNF-2 and GNF-5. ABL001 is ~100-fold more potent than GNF-2, but retains exquisite selectivity for ABL kinase compared to other kinases and also outside the kinase family. This probe retains potency for inhibition of BCR-ABL even in the context of all catalytic site mutations including T315I. ABL001 is efficacious as a single agent for use in both cells and animal models, and is currently being explored in combinations with active site inhibitors such as nilotinib, imatinib, and dasatinib. It should provide a valuable tool to the field for the study of BCR-ABL in the context of CML.

Reviewer Probe testing: ABL001 has been tested in our lab in the ABL1 NanoBRET TE assay using tracer K4. It demonstrated an IC50 of 2nM in HEK293 cells. This is consistent with recommended concentrations of up to 250nM.

Jan 7 2021 - 11:33am

NMR and X-Ray crystallography studies confirmed that ABL001 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; GNF-2 displayed a profile analogous to ABL001 but is ~100-fold less potent.

Jan 19 2021 - 12:26pm

Asciminib

Probe Availability

Probe Information

Target Details

Dmel_CG4032, 4674, ABL1, AblK, Ableson, Am ABL, C-abl, CG4032, D-Abl, D-abl, D-ash, DAbl, DROTKABL3, Dabl, Dash, Ddash/abl, Dmel\CG4032, Dsrc7

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Asciminib

Probe Availability

Probe Information

Target Details

Dmel_CG4032, 4674, ABL1, AblK, Ableson, Am ABL, C-abl, CG4032, D-Abl, D-abl, D-ash, DAbl, DROTKABL3, Dabl, Dash, Ddash/abl, Dmel\CG4032, Dsrc7

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?