Concept of Targeted Drug Conjugate and Its Application in Reversing Drug Resistance

Small-molecule targeted drugs have become the mainstream cancer treatment due to their specific therapy. However, drug resistance inevitably happens to cancer patients. Herein, we propose the "targeted drug conjugate (TDC)" concept to design drugs that enhance antitumor activity, reduce toxicity, and reverse resistance. Upon this idea, compounds Lapa-603 and Lapa-604 were obtained by modifying Pt(II) units with Lapatinib's pharmacophore. Research has found that Lapa-604 can potently inhibit the proliferation of the tested cancer cells and reverse multiple cancer cell resistance by targeting the EGFR protein and causing severe DNA damage. More importantly, Lapa-604 presented higher tumor growth inhibitory efficacy than Lapatinib, Cisplatin, or their physical mixtures in both MDA-MB-231 and BT474 xenograft tumor models. Our research has provided promise for the design and development of novel drugs based on the TDC concept that can effectively overcome drug resistance with stronger antitumor activity and lower toxicity than the corresponding combination therapy.