Engel Julian, Smith Steven, Lategahn Jonas, Tumbrink Hannah L, Goebel Lisa, Becker Christian, Hennes Elisabeth, Keul Marina, Unger Anke, Müller Heiko, Baumann Matthias, Schultz-Fademrecht Carsten, Günther Georgia, Hengstler Jan G, Rauh Daniel
Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, D-44227 Dortmund, Germany.
Lead Discovery Center GmbH , Otto-Hahn-Straße 15, D-44227 Dortmund, Germany.
J Med Chem. 2017 Sep 28;60(18):7725-7744. doi: 10.1021/acs.jmedchem.7b00515. Epub 2017 Sep 18.
Reversible epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance. These inhibitors exhibited strong inhibitory effects toward EGFR kinase activity and excellent inhibition of cell growth in the drug-resistant cell line H1975, without significantly affecting EGFR wild-type cell lines. Additionally, we present the in vitro ADME/DMPK parameters for a subset of the inhibitors as well as in vivo pharmacokinetics in mice for a candidate with promising activity profile.
可逆性表皮生长因子受体（EGFR）抑制剂可使携带EGFR激活突变的非小细胞肺癌患者产生有益的临床反应。然而，耐药突变，尤其是守门人突变T790M，限制了这种疗效。在此，我们描述了一系列共价且对突变体具有选择性的EGFR抑制剂的结构导向开发，这些抑制剂可有效靶向T790M突变体。基于吡唑并嘧啶的核心在结构上与基于氨基嘧啶的第三代EGFR抑制剂不同，因此构成了一组针对这种耐药机制的新型抑制剂。这些抑制剂对EGFR激酶活性表现出强烈的抑制作用，并能有效抑制耐药细胞系H1975中的细胞生长，而对EGFR野生型细胞系没有显著影响。此外，我们还给出了部分抑制剂的体外ADME/DMPK参数，以及对具有良好活性谱的候选抑制剂在小鼠体内的药代动力学情况。
