Abstract:
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
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,Murradoi
10.1021/acs.jmedchem.6b01894subject
Has Abstractpub_date
2017-04-13 00:00:00pages
3002-3019issue
7eissn
0022-2623issn
1520-4804journal_volume
60pub_type
杂志文章abstract::A series of 6-alkyl-3 beta-benzyl-2-[(methoxycarbonyl)methyl]tropane analogues were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter (DAT). The in vitro affinity (Ki) for the DAT of the 6-alkyl-3 beta-benzyl-2-[(methoxycarbonyl) methyl]tropane analogues was determined by inhibition...
journal_title:Journal of medicinal chemistry
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doi:10.1021/jm00217a004
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journal_title:Journal of medicinal chemistry
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doi:10.1021/jm00150a024
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journal_title:Journal of medicinal chemistry
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doi:10.1021/jm00241a010
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journal_title:Journal of medicinal chemistry
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journal_title:Journal of medicinal chemistry
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doi:10.1021/jm00188a015
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pub_type: 杂志文章
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更新日期:1981-02-01 00:00:00