Crenolanib (CP-868596)

Catalog No.S2730

Crenolanib (CP-868596) is a potent and selective inhibitor of PDGFRα/β with Kd of 2.1 nM/3.2 nM in CHO cells, also potently inhibits FLT3, sensitive to D842V mutation not V561D mutation, >100-fold more selective for PDGFR than c-Kit, VEGFR-2, TIE-2, FGFR-2, EGFR, erbB2, and Src.

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Crenolanib (CP-868596) Chemical Structure

Crenolanib (CP-868596) Chemical Structure
Molecular Weight: 443.54

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Product Description

Biological Activity

Description Crenolanib (CP-868596) is a potent and selective inhibitor of PDGFRα/β with Kd of 2.1 nM/3.2 nM in CHO cells, also potently inhibits FLT3, sensitive to D842V mutation not V561D mutation, >100-fold more selective for PDGFR than c-Kit, VEGFR-2, TIE-2, FGFR-2, EGFR, erbB2, and Src.
Targets PDGFRα [1]
(CHO cells)
PDGFRβ [1]
(CHO cells)
IC50 2.1 nM(Kd) 3.2 nM(Kd)
In vitro Crenolanib is significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRα kinases (D842I, D842V, D842Y, D1842-843IM, and deletion I843). Crenolanib is 135-fold more otent than imatinib against D842V in the isogenic model system, with an IC50 of approximately 10 nM. Crenolanib inhibits the kinase activity of the fusion oncogene in EOL-1 cell line, which is derived from a patient with chronic eosinophilic leukemia and expresses the constitutively activated FIP1L1- PDGFRα fusion kinase, with IC50 = 21 nM. Crenolanib also inhibits the proliferation of EOL-1 cells with IC50 = 0.2 pM. Crenolanib inhibits the activation of V561D or D842V-mutant kinases expressed in BaF3 cells with IC50 with 85 nM or 272 nM, respectively. Crenolanib inhibits PDGFRα activation in H1703 non-small cell lung cancer cell line which has 24-fold amplification of the 4q12 region that contains the PDGFRα locus, with IC50 with 26 nM. [1] Crenolanib is an orally bioavailable, highly potent and selective PDGFR TKI. Crenolanib is a benzimidazole compound that has IC50s of 0.9 nM and 1.8 nM for PDGFRA and PDGFRB, respectively. [2]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
HL60MkiwS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?NUC4UolxUUN3ME2xxtExNjB|IN88US=>NYG2TXRGOjV3OUe3OVQ>
HL60/VCRMo\zS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MVfJR|UxRTZwOURCtVAvODNizszNM1yzTVI2PTl5N{W0
K562NX;HeGZ{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NHfjbVJKSzVyPUGuN:KyOC5yMzFOwG0>MnnwNlU2QTd5NUS=
K562/ABCB1MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?NFHjXZNKSzVyPUSuOlfDuTBwMEGg{txONXz2WINlOjV3OUe3OVQ>
K562/ABCG2MljrS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?NXiwV4xlUUN3ME2xMlU1yrFyLkCzJO69VQ>?NXrSUZluOjV3OUe3OVQ>
HL60MofvS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MUTJR|UxRTFwNEdCtVAvODRizszNM4nZUVI2PTl5N{W0
HL60/ADRMmjlS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?NWG1TWRzUUN3ME2xMlczyrFyLkC2JO69VQ>?MYmyOVU6Pzd3NB?=
HL60MXXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?NH;aV5pKSzVyPUCuPFbDuTBwMEKg{txONHTmVHkzPTV7N{e1OC=>
HL60+PSC-833MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?NEPxbJdKSzVyPUGuN|LDuTBwME[g{txOMkLqNlU2QTd5NUS=
HL60/VCRMUXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?M3XOZ2lEPTB;Nj6yO:KyOC5yMjFOwG0>M{DsNVI2PTl5N{W0
HL60/VCR+PSC-833NGjFdG5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=MYLJR|UxRTBwOEVCtVAvODRizszNMUCyOVU6Pzd3NB?=
K562NYmxcFh7T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NFLXVJBKSzVyPUKuNFLDuTBwMEWg{txONY\seWR5OjV3OUe3OVQ>
K562+PSC-833MVvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MmDmTWM2OD1{LkCyxtExNjB6IN88US=>NHTJVZAzPTV7N{e1OC=>
K562/ABCB1NF[yd2dIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=MV3JR|UxRTRwNEpCtVAvODRizszNMonDNlU2QTd5NUS=
K562/ABCB1+PSC-833Mni5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MnzmTWM2OD1{LkC2xtExNjB6IN88US=>Mn75NlU2QTd5NUS=
A549 MnHvS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M2Xqe|AuOTByMDDuUS=>MVGyOE81QC95MjDoM13QOYlvcGmkaYTzJINmdGxiZ4Lve5RpKGSxc3WgZY5lKHSrbXWg[IVx\W6mZX70cJk>NYDVc3ZrOjV|Mki0NFk>
A549NV6zfGhMSXCxcITvd4l{KEG|c3H5NIrFWJU2ODBibl2=MUW0PEBpMlTybY5lfWOnczDj[YxtKGGyb4D0c5Nqew>?MXeyOVMzQDRyOR?=
A549MUHGeY5kfGmxbjDBd5NigQ>?MknQNVIvPS9{NT:1NEBvVQ>?M1z2dlExKGh?NYD3[llvcW6qaXLpeJMh[2WubDDtbYdz[XSrb36=NITHSW8zPTN{OESwPS=>
M21Mn35RZBweHSxc3nzJGF{e2G7NFHDe2syKM7:TR?=MorFNlQhcA>?MYPpcoR2[2W|IHPlcIwh[XCxcITvd4l{KHOrZ37p[olk[W62bImgZ49u[mmwZXSge4l1cCC4ZX31doFn\W6rYh?=NWLEU244OjR5M{KxO|I>
M21RMlfDRZBweHSxc3nzJGF{e2G7NGDDPJYyKM7:TR?=MojmNlQhcA>?NELWSXhqdmS3Y3XzJINmdGxiYYDvdJRwe2m|IIPp[45q\mmlYX70cJkh[2:vYnnu[YQhf2m2aDD2[Y12emGoZX7pZi=>NF\MNlMzPDd|MkG3Ni=>
TPF-10-741MoTBRZBweHSxc3nzJGF{e2G7MVqxJO69VQ>?MnLJNlQhcA>?MXvpcoR2[2W|IHPlcIwh[XCxcITvd4l{KHOrZ37p[olk[W62bImgZ49u[mmwZXSge4l1cCC4ZX31doFn\W6rYh?=M33MVVI1PzN{MUey
Ba/F3 ITDNF35Wo9Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NW\Wc|lIUUN3ME2xMlMh|ryPM2njfVI1OjJ5OEKw
Ba/F3 ITD/D835YNV[3T3VqT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NEPvW3lKSzVyPUiuO{DPxE1?NEHxO4gzPDJ{N{iyNC=>
Ba/F3 WT D835YNXvVblN5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M4nWRWlEPTB;Nj65JO69VQ>?MkGyNlQzOjd6MkC=
Ba/F3 WT D835FNHzKN3ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=M{\EOWlEPTB;Nj61JO69VQ>?NYnBN4VMOjR{Mke4NlA>
Ba/F3 WT D835HMknUS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MXrJR|UxRTF7Lkig{txOMkX3NlQzOjd6MkC=
Ba/F3 WT D835NMmDsS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?NFjRWWdKSzVyPUSuN{DPxE1?NVzyV|czOjR{Mke4NlA>
Ba/F3 WT D835VNVLabm5iT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M2jCZWlEPTB;Mj6zJO69VQ>?NYPLPZRNOjR{Mke4NlA>
Ba/F3 ITD/F691LNYTRS|lVT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M1fGeGlEPTB;NkeuPEDPxE1?M2D0OFI1OjJ5OEKw
MV4-11NF\qS2ZE\WyuIG\pZYJtcXS7IFHzd4F6MYCwMVEh|ryPMl3nO|IhcA>?M3jtPYlvcGmkaYTzJINmdGxidnnhZoltcXS7IHTvd4Uh\GWyZX7k[Y51dHl?MUOyOFA1PjBzNB?=
MOLM-13MlnDR4VtdCCYaXHicIl1gSCDc4PhfS=>MmjuNE0yKM7:TR?=M{Cwb|czKGh?MnnubY5pcWKrdIOgZ4VtdCC4aXHibYxqfHliZH;z[UBl\XCnbnTlcpRtgQ>?MXOyOFA1PjBzNB?=
PL21NXq5UnJDS2WubDDWbYFjdGm2eTDBd5NigQ>?NHjKbnYxNTFyMDFOwG0>MlnmO|IhcA>?Ml\hbY5pcWKrdIOgZ4VtdCC4aXHibYxqfHliZH;z[UBl\XCnbnTlcpRtgQ>?Mlu0NlQxPDZyMUS=
OCI-AML3NV76bmNnS2WubDDWbYFjdGm2eTDBd5NigQ>?MnrYNE0yODBizszNM2rqWVczKGh?MnOxbY5pcWKrdIOgZ4VtdCC4aXHibYxqfHliZH;z[UBl\XCnbnTlcpRtgQ>?NEHqWHEzPDB2NkCxOC=>
THP-1M{LwZWNmdGxiVnnhZoxqfHliQYPzZZk>NG\DNWIxNTFyMDFOwG0>M1fmUlczKGh?MWDpcohq[mm2czDj[YxtKH[rYXLpcIl1gSCmb4PlJIRmeGWwZHXueIx6NEnoR4YzPDB2NkCxOC=>
U937M4H3WmNmdGxiVnnhZoxqfHliQYPzZZk>NHjKXpAxNTFyMDFOwG0>M2\I[VczKGh?M2\VV4lvcGmkaYTzJINmdGxidnnhZoltcXS7IHTvd4Uh\GWyZX7k[Y51dHl?NH\Uco8zPDB2NkCxOC=>

... Click to View More Cell Line Experimental Data

In vivo
Features

Protocol(Only for Reference)

Kinase Assay:

[1]

Biochemical Assessment of PDGFRα Kinase Activity Chinese hamster ovary (CHO) cells are transiently transfected with mutated or wild type PDGFRα constructs and treated with various concentrations of Crenolanib. Experiments involving recombinant DNA are performed using biosafety level 2 conditions in accordance with guidelines. Protein lysates from cell lines are prepared and subjected to immunoprecipitation using anti-PDGFRα antibodies followed by sequential immunoblotting for PDGFRα. Densitometry is performed to quantify drug effect using Photoshop software, with the level of phosphor- PDGFRα normalized to total protein. Densitometry and proliferation experimental results are analyzed using Calcusyn 2.1 software to mathematically determine the IC50 values. The Wilcoxon Rank Sum Test is used to compare the IC50 values of Crenolanib for a given mutation.

Cell Assay:

[1]

Cell lines EOL-1 cell line
Concentrations 0-20 pM
Incubation Time 72 hours
Method

Cells are added to 96-well plates at densities of 20, 000 cells/well and incubated with Crenolanib for 72 hours before measuring cellular proliferation using a 2,3-bis[2-methoxyl-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide (XTT)-based assay.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Heinrich MC, et al, Clin Cancer Res, 2012, Jun 27.

[2] Heinrich M, et al, AACR, 2011, Abstract 3586.

Chemical Information

Download Crenolanib (CP-868596) SDF
Molecular Weight (MW) 443.54
Formula

C26H29N5O2

CAS No. 670220-88-9
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms ARO 002
Solubility (25°C) * In vitro DMSO 89 mg/mL warming (200.65 mM)
Ethanol 7 mg/mL (15.78 mM)
Water <1 mg/mL (<1 mM)
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 1-(2-(5-((3-methyloxetan-3-yl)methoxy)-1H-benzo[d]imidazol-1-yl)quinolin-8-yl)piperidin-4-amine

Customer Product Validation(4)


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Rating
Source Proc Natl Acad Sci U S A 2014 111(14), 5319-24. Crenolanib (CP-868596) purchased from Selleck
Method Western blot
Cell Lines HB119, Molm14 cells
Concentrations 100 nM
Incubation Time 1 h
Results As crenolanib has been reported to bind kinases in a type I manner as evidenced by its relative affinity for phosphorylated versus nonphosphorylated ABL, it assessed the ability of crenolanib to inhibit FLT3 phosphorylation and downstream signaling in a D835-mutant acute-lymphoblastic-leukemia-patient-derived cell line, HB119, which harbors a FLT3 D835H activating mutation in the absence of an ITD. HB119 and Molm14 cell lines underwent apoptosis in the presence of crenolanib, whereas control cell lines were minimally affected.

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Rating
Source Clin Cancer Res 2013 19(24), 6935-42. Crenolanib (CP-868596) purchased from Selleck
Method Western blot
Cell Lines Ba/F3 cells
Concentrations 0-1 uM
Incubation Time 90 min
Results Crenolanib showed stronger inhibitory effect than imatinibon P577S, V658A, R841K, and H845Y.

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Rating
Source Mol Cancer 2014 13(1), 247. Crenolanib (CP-868596) purchased from Selleck
Method Western blot
Cell Lines GBM cancer stem cells
Concentrations 10 uM
Incubation Time 1, 2 days
Results Western blots analysis clearly showed an induction of Caspase-3 and PARP-1 cleavage fragments, the effect of which was maximized by combining the two inhibitors (A). Of note, is the de-repression of PDGFRα in AG1478-treated CSC1 as well as in p-CSC2 (B), this is probably due to a compensatory activation mechanism to evade EGFR TKI. In addition, it detected a downmodulation of PDGFRα expression following Crenolanib treatment, which was a common feature in all cases examined (A-C).

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Rating
Source Onco Targets Ther 2014 7, 1761-8. Crenolanib (CP-868596) purchased from Selleck
Method Hoechst
Cell Lines A549 cells
Concentrations 500 nM
Incubation Time 48 h
Results It further tested whether treatment of crenolanib was capable of inducing apoptosis in cancer cells. After treatment with crenolanib for 48 hours, the sub-G1 DNA content of A549 cells was measured as an indicator of late stage apoptosis. Apoptosis-induced condensed and fragmented DNA is visualized in figure.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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