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Altiratinib Trk receptor inhibitor

Cat.No.S6412

Altiratinib (DCC-2701) is a potent single-digit nanomolar inhibitor of TRK, Met (c-Met), TIE2, and VEGFR2 kinases with IC50 vaules of 0.9 nM, 4.6 nM, and 0.8 nM for TRKA, B, and C, respectively. This compound inhibits Met (c-Met) and Met (c-Met) mutant with IC50 values in the range of 0.3-6 nM.
Altiratinib Trk receptor inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 510.46

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Quality Control

Batch: S641201 DMSO]100 mg/mL]false]Water]Insoluble]false]Ethanol]Insoluble]false Purity: 99.82%
99.82

Solubility

In vitro
Batch:

DMSO : 100 mg/mL (195.9 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 510.46 Formula

C26H21F3N4O4

 Storage (From the date of receipt) 3 years -20°C powder
CAS No. 1345847-93-9 -- Storage of Stock Solutions

Synonyms DCC-2701 Smiles C1CC1C(=O)NC2=NC=CC(=C2)OC3=C(C=C(C(=C3)F)NC(=O)C4(CC4)C(=O)NC5=CC=C(C=C5)F)F

Mechanism of Action

Targets/IC50/Ki
MET Y1230C
(Cell-free assay)
0.37 nM
TrkA
(Cell-free assay)
0.85 nM
TrkC
(Cell-free assay)
0.85 nM
MET Y1230C
(Cell-free assay)
1.2 nM
MET D1228N
(Cell-free assay)
1.3 nM
MET Y1230H
(Cell-free assay)
1.5 nM
Met
(Cell-free assay)
2.7 nM
MET D1228H
(Cell-free assay)
3.6 nM
TrkB
(Cell-free assay)
4.6 nM
MET M1250T
(Cell-free assay)
6 nM
Tie2
(Cell-free assay)
8 nM
VEGFR2
(Cell-free assay)
9.2 nM
Flt-3
(Cell-free assay)
9.3 nM
Flt-3
(Cell-free assay)
9.3 nM
FMS
(Cell-free assay)
32 nM
KIT
(Cell-free assay)
68 nM
In vitro

Altiratinib is >10-fold selective for MET versus FMS and KIT, and >50-fold selective for MET versus ABL1, FYN, HER1 (EGFR), p38α (MAPK14), PDGFRα, PDGFRβ, RET, and SRC. This compound exhibits IC50s of 0.69 nmol/L in K562 cells, 1.2 nmol/L in SK-N-SH cells for inhibition of NGF-stimulated TRKA phosphorylation. It inhibits constitutive TRKA phosphorylation with an IC50 of 1.4 nmol/L in KM-12 cells. This chemical inhibits HGF-stimulated MET phosphorylation in HUVECs, exhibiting an IC50 of 2.3 nmol/L. In ANG1-stimulated HUVECs and EA.hy926 cells, it exhibits IC50 values of 1.0 nmol/L and 2.6 nmol/L, respectively, for inhibition of TIE2 phosphorylation. In VEGF-stimulated HUVECs, it inhibits VEGFR2 phosphorylation with an IC50 of 4.7 nmol/L. This compound potently inhibits cellular proliferation in MET-amplified EBC-1 and MKN-45 cells, as well as TPM3-TRKA fusion KM-12 cells, but only weakly inhibits other cancer cell lines, including proliferation of M-NFS-60 (IC50, 770 nmol/L); A375, BT-474, HCT-116, PC-3, SK-MEL-28, U87, and A549 cells (IC50s > 1,000 nmol/L).
In vivo

Altiratinib alone and in combination with bevacizumab increases survival and decreases circulating TIE2+-expressing monocytes in the U87 glioma model. In the PyMT syngeneic mammary tumor model which recapitulates many features of human breast cancer, this compound alone and in combination with paclitaxel inhibits PyMT mammary tumor growth, reduces tumoral TIE2+ stromal cell density, and inhibits lung metastasis. It achieves a brain:plasma ratio of 0.23 after systemic dosing, indicating significant penetration of the murine blood-brain barrier.
References

Clinical Trial Information

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

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02228811 Terminated
Locally Advanced Tumors|Metastatic Solid Tumors|Cancers With MET Genomic Alterations|Cancers With TRK Genomic Alterations
Deciphera Pharmaceuticals LLC
 June 2014 Phase 1

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