PF-06459988 - CAS 1428774-45-1
Catalog number: B0084-475427
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
Molecular Weight:
PF-06459988 is a third-generation, irreversible epidermal growth factor receptor (EGFR) inhibitor. It can bind to and inhibit mutant forms of EGFR, including the secondary acquired resistance mutation T790M.PF-06459988 may have therapeutic benefits in tumors with T790M-mediated drug resistance. Preclinical trials in Non-small cell lung cancer in USA is on-going.
white to beige powder
PF-06459988; PF06459988; PF 06459988; PF-6459988; PF 6459988; PF6459988; 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
DMSO: soluble5 mg/mL, clear
-20°C Freezer
Non-small cell lung cancer
Quality Standard:
In-house standard
Shelf Life:
2 month in rt, long time
Canonical SMILES:
Current Developer:
Originator Pfizer
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.
Cheng H;Nair SK;Murray BW;Almaden C;Bailey S;Baxi S;Behenna D;Cho-Schultz S;Dalvie D;Dinh DM;Edwards MP;Feng JL;Ferre RA;Gajiwala KS;Hemkens MD;Jackson-Fisher A;Jalaie M;Johnson TO;Kania RS;Kephart S;Lafontaine J;Lunney B;Liu KK;Liu Z;Matthews J;Nagata A;Niessen S;Ornelas MA;Orr ST;Pairish M;Planken S;Ren S;Richter D;Ryan K;Sach N;Shen H;Smeal T;Solowiej J;Sutton S;Tran K;Tseng E;Vernier W;Walls M;Wang S;Weinrich SL;Xin S;Xu H;Yin MJ;Zientek M;Zhou R;Kath JC J Med Chem. 2016 Mar 10;59(5):2005-24. doi: 10.1021/acs.jmedchem.5b01633. Epub 2016 Jan 28.
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. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. 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.
2.Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR.
Planken S;Behenna DC;Nair SK;Johnson TO;Nagata A;Almaden C;Bailey S;Ballard TE;Bernier L;Cheng H;Cho-Schultz S;Dalvie D;Deal JG;Dinh DM;Edwards MP;Ferre RA;Gajiwala KS;Hemkens M;Kania RS;Kath JC;Matthews J;Murray BW;Niessen S;Orr ST;Pairish M;Sach NW;Shen H;Shi M;Solowiej J;Tran K;Tseng E;Vicini P;Wang Y;Weinrich SL;Zhou R;Zientek M;Liu L;Luo Y;Xin S;Zhang C;Lafontaine J J Med Chem. 2017 Apr 13;60(7):3002-3019. doi: 10.1021/acs.jmedchem.6b01894. Epub 2017 Mar 29.
Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.
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