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.

小分子靶向药物凭借其特异性治疗作用，已成为癌症治疗的主流手段。然而，癌症患者不可避免地会出现耐药性问题。本研究中，我们提出“靶向药物偶联物（targeted drug conjugate, TDC）”的概念，用于设计可增强抗肿瘤活性、降低毒性并逆转耐药的药物。基于该设计理念，我们通过将铂(II)（Pt(II)）单元与拉帕替尼（Lapatinib）的药效团相结合，得到了化合物Lapa-603与Lapa-604。研究表明，Lapa-604可通过靶向表皮生长因子受体（EGFR）并引发严重的DNA损伤，强效抑制受试癌细胞的增殖，同时逆转多种癌细胞的耐药性。尤为重要的是，在MDA-MB-231与BT474异种移植肿瘤模型中，Lapa-604的肿瘤生长抑制效果均优于拉帕替尼、顺铂（Cisplatin）以及二者的物理混合物。本研究为基于TDC概念的新型药物设计与开发提供了可期的前景：这类药物可比对应联合疗法具备更强的抗肿瘤活性与更低的毒性，从而有效克服肿瘤耐药性。