| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
PF-06459988 targets the epidermal growth factor receptor (EGFR), specifically mutant forms of EGFR including those containing the T790M gatekeeper mutation. EGFR is a receptor tyrosine kinase that can be mutated in various tumor cell types and plays a key role in tumor cell proliferation and angiogenesis. First-generation EGFR TKIs (gefitinib, erlotinib) provide clinical benefit for NSCLC patients with oncogenic EGFR mutations, but disease progression often occurs due to the T790M second-site mutation. PF-06459988 is a third-generation irreversible inhibitor that covalently binds to EGFR mutants, demonstrating (i) high potency and specificity to T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity, and (iv) minimal activity against WT EGFR.
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| ln Vitro |
In NSCLC cell lines, PF-06459988 (0–10 μM; 2-hour duration) showed good cellular effectiveness and strong selectivity between the powerful target and WT EGFR[1]. NSCLC cell line concentration: 0–10 μM Incubation period: 2 hours; IC50 values of 13, 7, 21, 140, 90, and 5100 nM, respectively, indicate excellent results for H1975 (L858R/T790M), PC9-DRH (Del/T790M), H3255 (L858R), PC9 (Del), HCC827 (Del) (cell potency), and A549 (WT) cell lines. demonstrates excellent selectivity for T790M-containing double mutant EGFR.
PF-06459988 demonstrates potent in vitro activity against T790M-containing EGFR mutants. In NSCLC cell lines, PF-06459988 (0–10 μM; 2-hour duration) showed good cellular effectiveness and strong selectivity between the target and wild-type EGFR. The compound exhibits IC50 values of 13 nM for H1975 (L858R/T790M), 7 nM for PC9-DRH (Del/T790M), 21 nM for H3255 (L858R), 140 nM for PC9 (Del), 90 nM for HCC827 (Del), and 5100 nM for A549 (WT) cells. These results demonstrate excellent selectivity for T790M-containing double mutant EGFR over wild-type EGFR. The compound's irreversible binding mechanism ensures sustained inhibition of its target. |
| ln Vivo |
PF-06459988 has been evaluated in preclinical models and clinical trials for its antitumor activity. The mutation-selective EGFR inhibitor PF-06459988 is an orally administered, small-molecule, third-generation irreversible EGFR mutant inhibitor with potential antitumor activity. The compound specifically binds to and inhibits EGFR mutants, including the T790M mutation, thereby blocking EGFR-mediated signaling and leading to the death of EGFRm-expressing tumor cells. PF-06459988 has a therapeutic advantage against T790M-mediated resistant tumors compared to some other EGFR inhibitors. The compound has extremely low activity against wild-type EGFR and does not cause the dose-limiting toxicities associated with non-selective EGFR inhibitors. PF-06459988 was being investigated in the clinical trial NCT02297425 (a study in lung cancer patients with EGFRm).
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| Enzyme Assay |
The in vitro enzyme inhibition assay for PF-06459988 measures the inhibition of EGFR kinase activity using recombinant EGFR enzymes, including wild-type and mutant forms (L858R, T790M, Del). Varying concentrations of PF-06459988 (typically ranging from nanomolar to micromolar) are incubated with the enzyme, ATP, and a peptide substrate. The kinase reaction is allowed to proceed for a fixed period, and the extent of substrate phosphorylation is quantified. IC50 values are determined by fitting dose-response curves to the inhibition data. The compound is dissolved in DMSO and diluted in assay buffer to achieve the desired final concentrations. The covalent binding mechanism can be confirmed by pre-incubation studies or mass spectrometry. Appropriate positive controls and negative controls are included in each assay run.
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| Cell Assay |
The in vitro cellular assay for PF-06459988 is performed using NSCLC cell lines with various EGFR mutation statuses, including H1975 (L858R/T790M), PC9-DRH (Del/T790M), H3255 (L858R), PC9 (Del), HCC827 (Del), and A549 (WT). Cells are cultured in appropriate medium and treated with varying concentrations of PF-06459988 (0–10 μM) or vehicle control (DMSO) for 2 hours. Cell viability and proliferation are assessed using assays such as CellTiter-Glo or MTT. EGFR phosphorylation and downstream signaling (e.g., AKT, ERK) are assessed by Western blotting using phospho-specific antibodies. The differential sensitivity of mutant versus wild-type EGFR cell lines is evaluated to confirm target selectivity. IC50 values are determined for each cell line.
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| Animal Protocol |
In vivo animal experiments with PF-06459988 were likely conducted using immunocompromised mice bearing NSCLC xenografts with T790M-containing EGFR mutations. Tumor cells (e.g., H1975 or PC9-DRH) are implanted subcutaneously into the flank of nude or SCID mice. When tumors reach a predetermined size, animals are randomized into treatment groups receiving PF-06459988 or vehicle control. PF-06459988 is administered orally due to its oral bioavailability. Tumor volume is measured twice weekly using calipers, and body weight is monitored to assess tolerability. At study endpoint, tumors are harvested for analysis of EGFR phosphorylation, downstream signaling, and markers of proliferation and apoptosis. The compound's antitumor efficacy is evaluated by comparing tumor growth in treated versus control groups.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic (PK) parameters for PF-06459988 are partially documented. The compound is orally bioavailable. PF-06459988 has a molecular weight of 431.88 and a chemical formula of C19H22ClN7O3. The compound is soluble in DMSO at 50 mg/mL (115.77 mM) with ultrasonic assistance. The compound should be stored at -20°C in a dry, dark environment for up to 1 year. Stock solutions are stable at 0-4°C for up to 1 month. Detailed PK parameters including half-life, clearance, volume of distribution, and maximum concentration (Cmax) are available in the primary literature and should be consulted for specific experimental planning.
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| Toxicity/Toxicokinetics |
Comprehensive toxicological data for PF-06459988 are partially documented from preclinical and clinical studies. PF-06459988 has extremely low activity against wild-type EGFR and does not cause the dose-limiting toxicities associated with non-selective EGFR inhibitors. The compound has greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors. As a research-grade compound, PF-06459988 is intended for laboratory research purposes only and is not approved for human therapeutic use. Standard laboratory safety practices should be followed when handling this compound. Comprehensive toxicological profiling is available from clinical trial data and should be consulted for safety information.
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| References | |
| Additional Infomation |
PF-06459988 is being investigated in the clinical trial NCT02297425 (a study in lung cancer patients with EGFRm (epidermal growth factor receptor mutation)). The mutation-selective EGFR inhibitor PF-06459988 is an orally administered, small-molecule, third-generation irreversible epidermal growth factor receptor (EGFR) mutant (EGFRm) inhibitor with potential antitumor activity. The EGFR inhibitor PF-06459988 specifically binds to and inhibits EGFR mutants, including the secondary acquired resistance mutation T790M, thereby blocking EGFR-mediated signaling and leading to the death of EGFRm-expressing tumor cells. Compared to some other EGFR inhibitors, PF-06459988 may have a therapeutic advantage against T790M-mediated resistant tumors. This drug has extremely low activity against wild-type EGFR (WT EGFR) and does not cause the dose-limiting toxicities associated with non-selective EGFR inhibitors (which also inhibit WT EGFR). EGFR is a receptor tyrosine kinase that can be mutated in various tumor cell types and plays a key role in tumor cell proliferation and tumor angiogenesis.
PF-06459988 is a research compound developed for studying third-generation EGFR inhibition and for treating T790M-mediated resistance in NSCLC. The compound's high potency and specificity to T790M-containing double mutant EGFRs, minimal activity against wild-type EGFR, and reduced proteome reactivity make it a valuable tool for dissecting EGFR mutant-specific signaling. PF-06459988 was being investigated in the clinical trial NCT02297425 for lung cancer patients with EGFR mutations. The compound is also known as PF-6459988. PF-06459988 is available from various chemical suppliers for research purposes. Its utility lies in its ability to selectively inhibit T790M-containing EGFR mutants and overcome acquired resistance to first-generation EGFR TKIs. |
| Molecular Formula |
C19H22CLN7O3
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|---|---|
| Molecular Weight |
431.876081943512
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| Exact Mass |
431.147
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| CAS # |
1428774-45-1
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| Related CAS # |
(3S,4S)-PF-06459988;1858291-14-1
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| PubChem CID |
71535003
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| Appearance |
White to off-white solid powder
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| LogP |
1.8
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
30
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| Complexity |
629
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C(N1C[C@H](OC)[C@@H](COC2N=C(NC3=CN(C)N=C3)N=C3NC=C(Cl)C3=2)C1)(=O)C=C
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| InChi Key |
ODMXWZROLKITMS-RISCZKNCSA-N
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| InChi Code |
InChI=1S/C19H22ClN7O3/c1-4-15(28)27-7-11(14(9-27)29-3)10-30-18-16-13(20)6-21-17(16)24-19(25-18)23-12-5-22-26(2)8-12/h4-6,8,11,14H,1,7,9-10H2,2-3H3,(H2,21,23,24,25)/t11-,14+/m1/s1
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| Chemical Name |
1-((3R,4R)-3-(((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)-4-methoxypyrrolidin-1-yl)prop-2-en-1-one
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| Synonyms |
PF-6459988; PF-06459988; PF 6459988; PF06459988; PF6459988; PF 06459988;
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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 |
| 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) |
DMSO : ~50 mg/mL (~115.77 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (6.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.75 mg/mL (6.37 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.75 mg/mL (6.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3155 mL | 11.5773 mL | 23.1546 mL | |
| 5 mM | 0.4631 mL | 2.3155 mL | 4.6309 mL | |
| 10 mM | 0.2315 mL | 1.1577 mL | 2.3155 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.
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