1. Protein Tyrosine Kinase/RTK
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  2. PDGFR
    Autophagy

Crenolanib (Synonyms: CP-868596; CP 868596; CP868596)

Cat. No.: HY-13223 Purity: 99.78%
Data Sheet SDS Handling Instructions

Crenolanib is a potent and selective inhibitor of PDGFRα/β, FLT3 with Kd of 2.1 nM/3.2 nM, 0.74 nM, respectively, sensitive to D842V mutation not V561D mutation, and > 100-fold more selective for PDGFR than c-Kit, VEGFR-2, TIE-2, FGFR-2, EGFR, erbB2, and Src.

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Crenolanib Chemical Structure

Crenolanib Chemical Structure

CAS No. : 670220-88-9

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10 mM * 1 mL in DMSO $121 In-stock
5 mg $110 In-stock
10 mg $150 In-stock
50 mg $400 In-stock
100 mg $640 In-stock
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Description

Crenolanib is a potent and selective inhibitor of PDGFRα/β, FLT3 with Kd of 2.1 nM/3.2 nM, 0.74 nM, respectively, sensitive to D842V mutation not V561D mutation, and > 100-fold more selective for PDGFR than c-Kit, VEGFR-2, TIE-2, FGFR-2, EGFR, erbB2, and Src.

IC50 & Target

Kd: 2.1 nM (PDGFRα), 3.2 nM (PDGFRβ), 0.74 nM (FLT3)

In Vitro

Crenolanib has 25-fold more affinity for PDGFRA/B compared with KIT, and is approximately 135-fold more potent than imatinib for inhibiting the PDGFRA D842V mutation. The IC50 for crenolanib for a KIT exon 11 deletion mutant kinase is greater than 1,000 versus 8 nM for imatinib. Crenolanib has low nanomolar potency against the V561D + D842V-mutant kinase that is similar to its potency against the isolated D842V mutation. Both imatinib and crenolanib potently inhibit the kinase activity of the fusion oncogene with IC50 values of 1 and 21 nM, respectively, and inhibits PDGFRA activation in this cell line with IC50 values of 93 and 26 nM, respectively[1]. HL60/VCR and K562/ABCB1 cells, overexpressing ABCB1, are 6.9- and 3.6-fold resistant to crenolanib, respectively, in relation to parental HL60 and K562 cells. PSC-833 fully reverses resistance to crenolanib in both HL60/VCR and K562/ABCB1 cells. Crenolanib (1 nM-10 μM) stimulates ABCB1 ATPase activity in a concentration-dependent manner. Crenolanib treatment does not increase the cell surface expression of ABCB1. Crenolanib inhibits [125I]-IAAP photocrosslinking of ABCB1 at high concentrations, with 50 % inhibition at 10 μM, but has little effect at lower concentrations, below 1 μM[2]. Crenolanib decreases NSCLC cell viability, induces apoptosis in NSCLC cells, and inhibits cell migration in NSCLC cells[3].

In Vivo

Crenolanib (10 mg/kg and 20 mg/kg) suppresses non-small-cell lung cancer tumor growth in vivo and induces tumor cell apoptosis, and the dosage of crenolanib applied is well tolerated by recipient mice[3].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT01393912 St. Jude Children's Research Hospital|Arog Pharmaceuticals, Inc.|The V Foundation for Cancer Research Diffuse Intrinsic Pontine Glioma|Progressive or Refractory High-Grade Glioma July 2011 Phase 1
NCT02626364 Arog Pharmaceuticals, Inc. Recurrent/Refractory Glioblastoma April 2016 Phase 2
NCT01243346 Arog Pharmaceuticals, Inc. D842-related Mutant GIST April 2011 Phase 2
NCT02400255 Arog Pharmaceuticals, Inc. Acute Myeloid Leukemia September 2015 Phase 2
NCT01229644 Arog Pharmaceuticals, Inc. Glioma April 2011 Phase 2
NCT01522469 Arog Pharmaceuticals, Inc. Relapsed or Refractory Acute Myeloid Leukemia With FLT3 Activating Mutations July 2012 Phase 2
NCT02847429 Arog Pharmaceuticals, Inc.|Centre Leon Berard|Fox Chase Cancer Center GIST With D842V Mutated PDGFRA Gene August 2016 Phase 3
NCT02283177 Arog Pharmaceuticals, Inc. Newly Diagnosed AML With FLT3 Activating Mutations January 2015 Phase 2
NCT01657682 Arog Pharmaceuticals, Inc. Acute Myeloid Leukemia With FLT3 Activating Mutations That Has Relapsed or Been Refractory After One or More Prior Therapies October 2012 Phase 2
NCT00949624 Arog Pharmaceuticals, Inc. Advanced Solid Tumors December 2005 Phase 1
NCT02400281 Arog Pharmaceuticals, Inc. Acute Myeloid Leukemia September 2015 Phase 1|Phase 2
NCT02270788 St. Jude Children's Research Hospital|Arog Pharmaceuticals, Inc.|Ohio State University Acute Myeloid Leukemia April 2, 2015 Phase 1
NCT00386555 Arog Pharmaceuticals, Inc. Carcinoma, Non-Small-Cell Lung May 2007 Phase 2
NCT02298166 University of Ulm Acute Myeloid Leukemia November 17, 2016 Phase 3
NCT02626338 Arog Pharmaceuticals, Inc. Relapsed/Refractory Acute Myeloid Leukemia (AML) February 2016 Phase 1|Phase 2
NCT02829840 M.D. Anderson Cancer Center|Ariad Pharmaceuticals Leukemia|FLT3-Mutated Acute Myeloid Leukemia|FLT3-Mutated High-Risk Myelodysplastic Syndrome September 2016 Phase 1|Phase 2
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 2.2546 mL 11.2729 mL 22.5459 mL
5 mM 0.4509 mL 2.2546 mL 4.5092 mL
10 mM 0.2255 mL 1.1273 mL 2.2546 mL
Cell Assay
[2]

Viable cell numbers following drug treatment are measured using the WST-1 assay. Briefly, 1×103 cells are seeded in 100 μL complete medium per well in 96-well tissue culture plates and incubated with crenolanib (0-10 μM) at 37°C in 5% CO2 for 96 h. 10 μL WST-1 reagent is then added to each well, incubation is continued for two additional hours and the color developed is quantified according to the manufacturer’s instructions. Each experiment is performed in triplicate. IC50 concentrations are calculated by the least square fit of dose–response inhibition in a non-linear regression model using GraphPad Prism V software.

Animal Administration
[3]

Crenolanib is formulated in 10% 1-methyl-2-pyrrolidinone and 90% polyethylene glycol 300. 

A549 cells are injected into the axillary regions of mice (2×106 cells/mouse). When the tumor volumes reached 70 mm3, the mice are randomLy allocated to the control group, low-dose crenolanib group (10 mg/kg), or high-dose crenolanib group (20 mg/kg) (n=6 per group). The vehicle for crenolanib treatment consists of 10% 1-methyl-2-pyrrolidinone and 90% polyethylene glycol 300. The tumor size and mouse body weight are measured every other day for about 2 weeks. The tumor volume is calculated as follows: (mm3)=(width×width×length)/2. After treatment, the mice are euthanized using carbon dioxide, and the tumors are harvested and analyzed.

References
M.Wt

443.54

Formula

C₂₆H₂₉N₅O₂

CAS No.

670220-88-9

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

10 mM in DMSO

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 99.78%

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Crenolanib
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