PF-06747775, also known as mavelertinib, is an orally active, third-generation irreversible EGFR inhibitor developed by Pfizer. It has the formula C18H22FN9O2, a molecular weight of 415.43 g/mol, and defined (3R,4R) stereochemistry. CAS 1776112-90-3 identifies this stereoisomer. A stereospecific PF-06747775 SMILES representation is COc1nn(C)cc1Nc1nc(nc2n(C)cnc12)N1CC@@HC@@HNC(=O)C=C. Its terminal acrylamide enables covalent target engagement.
Application of PF-06747775
Mavelertinib PF-06747775 is used to investigate activating and resistance-associated EGFR mutations in NSCLC models. It supports studies of T790M-mediated resistance, Cys797 engagement, and mutant-versus-wild-type inhibition. It is also a reference for comparing irreversible third-generation TKIs and downstream AKT or ERK responses.
In Vitro
In cellular assays, the EGFR T790M inhibitor PF-06747775 inhibited exon 19 deletion, L858R, T790M/L858R, and T790M/exon 19 deletion EGFR with IC50 values of 5, 4, 12, and 3 nM, respectively. The wild-type EGFR IC50 was 307 nM, giving a 26- to 102-fold selectivity window. The reported hERG IC50 was above 100 μM. Potency remains protocol-dependent and should be compared under matched conditions.
In Vivo
Oral bioavailability was 60% in mice, 11% in rats, and 66% in dogs. After intravenous dosing, plasma half-lives were 0.56, 0.28, and 1.3 hours, respectively. Antitumor activity was reported in xenografts driven by single and double EGFR mutants.
Clinical evaluation of PF-06747775 mavelertinib included 65 patients with EGFR-mutant advanced NSCLC. Doses ranged from 25 to 600 mg once daily; the maximum tolerated dose was not determined, and the recommended Phase 2 dose was 200 mg. The objective response rate was 41.5%, median response duration was 11.09 months, and median progression-free survival in the 200 mg analysis group was 8.1 months. The study ended early for strategic and external-environment reasons, without a reported change in the risk-benefit profile. Mavelertinib remains investigational.
Biochemical and Physiological Actions
T790M increases EGFR affinity for ATP and reduces the effectiveness of earlier reversible inhibitors. PF-06747775 binds in the ATP site and positions its acrylamide to form a covalent bond with Cys797. This suppresses mutant EGFR kinase activity and downstream AKT and ERK phosphorylation. Lower wild-type EGFR potency provides selectivity but does not exclude wild-type effects at higher exposure.
Features and Benefits of PF-06747775
- Low-nanomolar activity against major activating and T790M-containing EGFR mutants.
- Covalent Cys797 engagement with a defined mutant-over-wild-type selectivity window.
- A documented mavelertinib SMILES string with specified (3R,4R) stereochemistry.
- Clinical and preclinical data supporting translational EGFR inhibitor comparisons.
The search phrase mavelertinib PF-06747775 IUPAC SMILES combines separate identifiers: an IUPAC name and a SMILES string. Confirm both, together with purity and stereochemical identity, against the product-specific certificate of analysis.
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