PF-06459988 (PF06459988) is an orally bioavailable, 3rd-generation, covalent/irreversible inhibitor of T790M-Containing EGFR Mutants with potential anticancer activity. First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.
Physicochemical Properties
| Molecular Formula | C19H22CLN7O3 |
| Molecular Weight | 431.876081943512 |
| Exact Mass | 431.147 |
| CAS # | 1428774-45-1 |
| Related CAS # | (3S,4S)-PF-06459988;1858291-14-1 |
| PubChem CID | 71535003 |
| Appearance | White to off-white solid powder |
| LogP | 1.8 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 30 |
| Complexity | 629 |
| Defined Atom Stereocenter Count | 2 |
| 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 |
| InChi Key | ODMXWZROLKITMS-RISCZKNCSA-N |
| 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 |
| 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 |
| Synonyms | PF-6459988; PF-06459988; PF 6459988; PF06459988; PF6459988; PF 06459988; |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| 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. |
| References |
[1]. Discovery of 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 (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants. J Med Chem. 2016 Mar 10;59(5):2005-24. doi: 10.1021/acs.jmedchem.5b01633. Epub 2016 Jan 28. |
| Additional Infomation |
PF-06459988 is under investigation in clinical trial NCT02297425 (A Study For Patients With EGFRm (Epidermal Growth Factor Receptor Mutant) Lung Cancer). Mutant-selective EGFR Inhibitor PF-06459988 is an orally available, small molecule, third-generation, irreversible inhibitor of epidermal growth factor receptor (EGFR) mutant (EGFRm) forms with potential antineoplastic activity. EGFR inhibitor PF-06459988 specifically binds to and inhibits mutant forms of EGFR, including the secondary acquired resistance mutation T790M, which prevents EGFR-mediated signaling and leads to cell death in EGFRm-expressing tumor cells. Compared to some other EGFR inhibitors, PF-06459988 may have therapeutic benefits in tumors with T790M-mediated drug resistance. This agent shows minimal activity against wild-type EGFR (WT EGFR), and does not cause dose-limiting toxicities that are seen with the use of non-selective EGFR inhibitors, which also inhibit WT EGFR. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~50 mg/mL (~115.77 mM) |
| 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. 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. 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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |