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.

中文翻译：

---

共价和突变体选择性吡唑并嘧啶对表皮生长因子受体的靶T790M耐药性的结构指导发展。

可逆性表皮生长因子受体（EGFR）抑制剂在具有EGFR激活突变的非小细胞肺癌患者中提示了有益的临床反应。但是，耐药性突变，特别是关守突变T790M，限制了这种功效。在这里，我们描述了一系列有效靶向T790M突变体的共价和突变体选择性EGFR抑制剂的结构指导开发。基于吡唑并嘧啶的核心与基于氨基嘧啶的第三代EGFR抑制剂在结构上有所不同，因此构成了针对这种耐药机制的一组新抑制剂。这些抑制剂在耐药性细胞株H1975中对EGFR激酶活性表现出强大的抑制作用，并对细胞生长具有出色的抑制作用，不会明显影响EGFR野生型细胞系。此外，我们提出了抑制剂的一个子集的体外ADME / DMPK参数，以及在小鼠中具有有希望的活性谱的体内药代动力学。