TL13-112

Protein target name:

ALK

Mechanism of action:

DegraderPROTAC

Recommended Concentration for use in cells:

250 nM, up to 1 uM

Probe Availability

TOCRIS

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

RTK

HUGO ID:

HGNC:427

Entrez gene ID:

238

UNIPROT ID:

Q9UM73

Target alias:

CD246; NBLST3

Probe Details

Chemical Probes Portal ID:

CPP2104

Probe alias:

cpd 11, PROTAC

PubChem CID:

138108958

ChEMBL ID:

CHEMBL4213986

SMILES string:

CC(OC1=CC(C2CCN(CC2)CCOCCOCCNC(CNC3=CC=CC4=C3C(N(C4=O)C5CCC(NC5=O)=O)=O)=O)=C(C=C1NC6=NC=C(C(NC7=CC=CC=C7S(=O)(C(C)C)=O)=N6)Cl)C)C

InChi Key:

XIRQUXILNXIWDI-UHFFFAOYSA-N

Control compound:

TL13-110

Orthogonal probe:

CeritinibBrigatinibCH5424802

Physico-chemical properties

NMR:

1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.59 (s, 1H), 9.46 (s, 1H), 8.44 (d, J = 8.5 Hz, 1H), 8.38 (br, 1H), 8.25 (s, 1H), 8.18 (dd, J = 6.0, 5.5 Hz, 1H), 8.09 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 8.5, 8.0 Hz, 1H), 7.57 (dd, J = 8.0, 7.5 Hz, 1H), 7.34 (dd, J = 8.5, 8.0 Hz, 1H), 7.06 (d, J = 6.0 Hz, 1H), 6.93 (dd, J = 5.5, 5.5 Hz, 1H), 6.84 (d, J = 9.0 Hz, 1H), 6.75 (s, 1H), 5.06 (dd, J = 13.0, 5.5 Hz, 1H), 4.48 (m, J = 6.0 Hz, 1H), 3.93 (d, J = 5.5 Hz, 2H), 3.78 (m, 2H), 3.59 (m, 4H), 3.56 (m, 2H), 3.44 (m, 4H), 3.28 (m, 2H), 3.13 (m, 4H), 2.83–2.99 (m, 2H), 2.52–2.61 (m, 1H), 2.13 (s, 3H), 1.85–2.04 (m, 4H), 1.22 (d, J = 6.0 Hz, 6H), 1.15 (d, J = 7.0 Hz, 6H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

0.6 nM

Potency assay:

ALK LANCE Activity Assay at ATP Km (18µM)

Structure-activity relationship:

In cell validation

On target activity in cells

Potency in cells:

DC50 @ 16h

10 nM (H3122), 40 nM (K-299), 50 nM (Kelly)

Potency assay (cells):

Immunoblots of dose titrated cell lysates TNT LC-MS

Target engagement assay (cells):

Pretreatment of the cell lines with the proteasome inhibitor carfilzomib prevented degradation of ALK and Aurora A

Mechanistic Control Experiment:

With control TL13-110

Phenotypic Control Experiment:

No degradation in cells pretreated with inhibitor of CRBL MLN4924 or parental kinase inhibitor; no degradation in presence of proteasome inhibitor

Off target activity in cells

Probe Selectivity in Cell:

Degradation of targets other than ALK, including PTK2, FER, RPS6KA1, and Aurora A, was measured at significant levels with proteomic MS and confirmed by Western blot.

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.7b01655

Reference (PMID):

29660984

TL13-112

Probe Availability

Probe Information

Target Details

CD246; NBLST3

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

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TL13-112

Probe Availability

Probe Information

Target Details

CD246; NBLST3

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?