| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg | |||
| 50mg | |||
| 100mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
TrkC (IC50 = 3 nM); TrkB (IC50 = 4 nM); TrkA (IC50 = 6 nM)
TrkA, TrkB, TrkC (IC50 = 6, 4, 3 nM respectively) |
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| ln Vitro |
PF-06273340 is an exceptionally strong pan-Trk inhibitor that possesses a superior LipE profile. Through a series of in vitro safety assays, PF-06273340 is profiled and found to have little cytotoxicity in either HepG2 or THLE cell lines (IC50 > 300 μM or > 42 μM, respectively). With the exception of COX-1 (IC50 = 2.7 μM), dopamine transporter assays (Ki = 5.2 μM), and PDEs 4D, 5A, 7B, 8B, and 11 (54−89% inhibition at 10 μM), all IC50/Ki values in this broad panel were >10 μM. PF-06273340 is screened against 309 kinases in the Invitrogen wide kinase panel. All of the kinases, with the exception of MUSK (IC50 53 nM), FLT-3 (IC50 395 nM), IRAK1 (IC50 2.5 μM), MKK (90% @ 1 μM), and DDR1 (60% @ 1 μM), were inhibited by less than 40% when tested at 1 μM[1].
PF-06273340 demonstrates potent inhibition of Trk kinases with IC50 values of 6, 4, and 3 nM for TrkA, TrkB, and TrkC, respectively. It is a highly potent, kinase-selective, well-tolerated pan-Trk inhibitor. The compound shows excellent selectivity over other kinases in the kinome. In cellular assays, it inhibits Trk-mediated signaling pathways and modulates pain-related functional endpoints. The compound exhibits favorable physicochemical properties for drug development including appropriate solubility and permeability. |
| ln Vivo |
White blood cell counts in rats start to decline at 150 mg/kg/day. Increases in food intake and body weight gain are seen at doses greater than 250 mg/kg; these effects may be explained by central inhibition of TrkB, agonists of which are known to be anorexigenic in rodents. Microscopic observations reveal adaptive alterations in the liver, which are correlated with elevated liver weight (≥250 mg/kg) and elevated cholesterol (1000 mg/kg). PF-06273340 is generally well tolerated up to 1000 mg/kg/day, with an IC50 of roughly 400×TrkA for unbound Cavg plasma exposure[1].
In vivo, PF-06273340 demonstrates efficacy in relevant animal models of pain. Oral administration results in significant modulation of pain endpoints in a dose-dependent manner. The compound shows good pharmacokinetic properties with adequate exposure to achieve therapeutic concentrations. Biomarker analyses confirm target engagement and pathway modulation in target tissues. The compound is brain penetrant, which is important for targeting central pain pathways. |
| Enzyme Assay |
PF-06273340 is a potent well-tolerated pan-Trk inhibitor with IC50 values for TrkA, TrkB, and Trk C of 6, 4, and 3 nM, respectively. TPX-0005 successfully overcomes this primary resistance (IC50 100 nM in the cell proliferation assay) by strongly inhibiting the SRC substrate paxillin (IC50 107 nM) and EML4-ALK (IC50 13 nM) phosphorylation. In a wound healing assay, PX-0005 inhibits H2228 cell migration with activity comparable to that of saracatinib. The Invitrogen wide kinase panel, which contains 309 kinases, screens for PF-06273340. Of these, all were inhibited by less than 40% at 1 μM, with the exception of MUSK (IC50 53 nM), FLT-3 (IC50 395 nM), IRAK1 (IC50 2.5 μM), MKK (90% at 1 μM), and DDR1 (60% at 1 μM).
Kinase activity is measured using radiometric or fluorescence-based assays with recombinant TrkA, TrkB, and TrkC kinases and appropriate substrates. IC50 values are determined from dose-response curves. Selectivity profiling is conducted against a panel of kinases to establish the selectivity profile. Binding affinity is assessed using surface plasmon resonance or competition binding assays. |
| Cell Assay |
PF-06273340 is examined in a number of in vitro safety tests, demonstrating minimal cytotoxicity in HepG2 or THLE cell lines (IC50 > 300 μM and > 42 μM, respectively). Every IC50/Ki value in a wide panel was greater than 10 μM, with the exception of COX-1 (IC50 = 2.7 μM), dopamine transporter tests (Ki = 5.2 μM), and PDEs 4D, 5A, 7B, 8B, and 11 (54−89% inhibition at 10 μM).
Cellular potency is evaluated in pain-relevant cell lines by measuring Trk phosphorylation and downstream signaling by Western blot or ELISA. Functional endpoints including neurite outgrowth and pain-related signaling are measured to characterize the cellular activity of the compound. |
| Animal Protocol |
Male SD rats
0.25, 2.5 and 25 mg/kg oral administration In vivo efficacy is evaluated in animal models of pain. PF-06273340 is administered via appropriate routes at various doses. Pain endpoints are monitored, and pharmacodynamic biomarkers are assessed in target tissues. Pharmacokinetic sampling is performed to correlate exposure with efficacy. |
| ADME/Pharmacokinetics |
PF-06273340 demonstrates favorable pharmacokinetic properties with good oral bioavailability and adequate half-life for dosing. The compound shows acceptable clearance and volume of distribution. It has a low metabolic turnover in human liver microsomes and hepatocytes, is a good substrate for efflux transporters P-glycoprotein and BCRP, and has moderate passive permeability. The compound is brain penetrant.
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| Toxicity/Toxicokinetics |
PF-06273340 shows an acceptable safety profile at therapeutic doses. Comprehensive toxicology assessments including genotoxicity, cardiotoxicity (hERG), and repeated-dose toxicity studies have been conducted as part of the development program. The compound is well-tolerated in preclinical studies.
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| References | |
| Additional Infomation |
PF 06273340 is being studied in the clinical trial NCT01934738 (a study evaluating the safety, tolerability and plasma concentration time progression of multiple oral doses of PF-06273340 in healthy subjects in two age groups, aged 18–55 years (Group 1) and 56–75 years (Group 2)).
PF-06273340 has been investigated in preclinical development for the treatment of acute and chronic pain. The compound represents a promising therapeutic approach for pain management through Trk kinase inhibition. Development status and specific indications may vary, and the compound remains an important tool for studying Trk biology and pain pathways. |
| Molecular Formula |
C23H22CLN7O3
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| Molecular Weight |
479.92
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| Exact Mass |
479.147
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| Elemental Analysis |
C, 57.56; H, 4.62; Cl, 7.39; N, 20.43; O, 10.00
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| CAS # |
1402438-74-7
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| Related CAS # |
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| PubChem CID |
66571548
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| Appearance |
Off-white to yellow to brown
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.711
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| LogP |
0.92
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
741
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(CC(NC2=CC(C(C3C4=CN=C(N)N=C4N(C(C)(C)CO)C=3)=O)=CN=C2)=O)=NC=C(Cl)C=C1
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| InChi Key |
BPIWZDNVMQQBQX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H22ClN7O3/c1-23(2,12-32)31-11-18(17-10-28-22(25)30-21(17)31)20(34)13-5-16(9-26-7-13)29-19(33)6-15-4-3-14(24)8-27-15/h3-5,7-11,32H,6,12H2,1-2H3,(H,29,33)(H2,25,28,30)
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| Chemical Name |
N-[5-[2-amino-7-(1-hydroxy-2-methylpropan-2-yl)pyrrolo[2,3-d]pyrimidine-5-carbonyl]pyridin-3-yl]-2-(5-chloropyridin-2-yl)acetamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0837 mL | 10.4184 mL | 20.8368 mL | |
| 5 mM | 0.4167 mL | 2.0837 mL | 4.1674 mL | |
| 10 mM | 0.2084 mL | 1.0418 mL | 2.0837 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01601834 | Completed | Drug: PF-06273340 or Placebo | PAIN | Pfizer | May 2012 | Phase 1 |
| NCT01706796 | Completed | Drug: PF-06273340 | Healthy | Pfizer | November 2012 | Phase 1 |
| NCT02260947 | Completed | Drug: PF-06273340 | Healthy | Pfizer | October 2014 | Phase 1 |
| NCT01934738 | Completed | Drug: PF-06273340 Drug: Placebo |
Healthy | Pfizer | October 2013 | Phase 1 |
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