Discovery of Dosimertinib, a Highly Potent, Selective, and Orally Efficacious Deuterated EGFR Targeting Clinical Candidate for the Treatment of Non-Small-Cell Lung Cancer

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 in vivo 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).