A-770041

Protein target name:

LCK

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

1-10 uM

Reviewer suggested Concentration for use in cells:

Potentiation of paclitaxel and doxorubicin was tested using 4 nM-10 uM in U-2OSMR and KHOSR2.

Probe Availability

MedChemExpress

Axon MedChem

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:6524

Entrez gene ID:

3932

UNIPROT ID:

P06239

Target alias:

LCK proto-oncogene, Src family tyrosine kinase, IMD22, LSK, YT16, p56lck, pp58lck

Probe Details

Chemical Probes Portal ID:

CPP1192

Probe alias:

A 770041, A770041, cpd 20, L2G

PubChem CID:

9549184

ChEMBL ID:

CHEMBL197603

SMILES string:

NC1=C2C(N([C@@H]3CC[C@@H](N4CCN(C(C)=O)CC4)CC3)N=C2C5=CC=C(NC(C6=CC7=C(C=CC=C7)N6C)=O)C(OC)=C5)=NC=N1

InChi Key:

ZMNWFTYYYCSSTF-UHFFFAOYSA-N

Orthogonal probe:

WH-4-023

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

147 nM @ 1 mM ATP

Potency assay:

Enzymatic inhibition assay

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

2C0O

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

A-770041 is 300-fold selective against Fyn, the other Src-family kinase involved in T-cell signaling. A-770041 exhibits >60-fold selectivity versus the Src and Fgr, and >8-fold versus Lyn and Hck. Selectivity against the receptor tyrosine kinases Tie-2 and Kdr was >340-fold. (Src 9.1, Fgr 14.1, Fyn 44.1 uM); Selective over ZAP-70, ITK and PKC

In cell validation

On target activity in cells

Potency in cells:

EC50

80 nM

Potency assay (cells):

Inhibition of Concanavalin A-induced cytokine production in Whole Blood

In vivo validation

Organism:

MouseRat

Dose:

10 mg/Kg PO5 mg/Kg IV

Route of delivery:

OralIntravenous

Plasma half life:

4.7 (M), 4.1 (R) h

Systemic clearance:

1.5 (M), 0.2 (R) L/h/Kg

Fraction of probe bound to plasma protein:

27(M), 52 (R) %

Cmax:

2079 (R) ng/mL387 (M) ng/mL

Tmax:

1 (M), 4.7 (R) h

Primary Reference

Reference (doi):

10.1016/j.bmcl.2005.09.039 10.1124/jpet.105.089169

Reference (PMID):

16216497 16014572

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

This is a selective probe within the src family of RTK’s as described. Selectivity outside this family has been mentioned, but data not provided. From JPET paper: “A-770041 is 60-fold selective against Src, 95-fold selective against Fgr, and 300-fold selective against Fyn. A-770041 was also greater than 200-fold selective against a secondary battery of approximately 20 serine/threonine and tyrosine kinases outside of the Src family and IC50 values greater than 10 uM in a CEREP panel of approximately 70 molecular targets (data not shown).”

Dec 18 2020 - 10:48am

Initial studies involving development and medicinal chemistry were performed against purified proteins (including selectivity panels) and in vivo in rats and mice. Two later studies used this probe in cells to potentiate chemotherapies, in which case a range of concentrations were tested, and to target an acute myeloid leukemia cell line known to have a mutant dysregulated Lck protein. The latter studies provide good evidence for cellular engagement of the target in a selective way.

Jan 19 2021 - 12:39pm

A-770041

Probe Availability

Probe Information

Target Details

LCK proto-oncogene, Src family tyrosine kinase, IMD22, LSK, YT16, p56lck, pp58lck

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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A-770041

Probe Availability

Probe Information

Target Details

LCK proto-oncogene, Src family tyrosine kinase, IMD22, LSK, YT16, p56lck, pp58lck

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?