College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
J Med Chem. 2021 Jan 28;64(2):925-937. doi: 10.1021/acs.jmedchem.0c02005. Epub 2021 Jan 18.
Osimertinib is a highly potent and selective third-generation epidermal growth factor receptor (EGFR) inhibitor, which provides excellent clinical benefits and is now a standard-of-care therapy for advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, AZ5104, a primary toxic metabolite of osimertinib, has caused unwanted toxicities. To address this unmet medical need, we initiated an iterative program focusing on structural optimizations of osimertinib and preclinical characterization, leading to the discovery of a highly potent, selective, and orally efficacious deuterated EGFR-targeting clinical candidate, dosimertinib. Preclinical studies revealed that dosimertinib demonstrated robust antitumor efficacy and favorable PK profiles, but with lower toxicity than osimertinib. These preclinical data support further clinical development of dosimertinib for the treatment of NSCLC. Dosimertinib has received official approval in China to initiate the phase I clinical trial (registration numbers: CXHL2000060 and CXHL2000061).
奥希替尼是一种高效且选择性的第三代表皮生长因子受体（EGFR）抑制剂，为晚期 EGFR 突变阳性非小细胞肺癌（NSCLC）患者提供了卓越的临床获益，现已成为标准治疗方案。然而，奥希替尼的主要毒性代谢物 AZ5104 引起了非预期的毒性。为了解决这一未满足的医疗需求，我们启动了一个迭代项目，专注于奥希替尼的结构优化和临床前特征描述，从而发现了一种高效、选择性和口服有效的氘代 EGFR 靶向临床候选药物，即多西替尼。临床前研究表明，多西替尼具有强大的抗肿瘤疗效和良好的药代动力学特征，但毒性低于奥希替尼。这些临床前数据支持进一步开发多西替尼用于 NSCLC 的治疗。多西替尼已在中国获得批准开展 I 期临床试验（注册号：CXHL2000060 和 CXHL2000061）。
