Small Molecule-Drug Conjugates: An Emerging Drug Design Strategy for Targeted Therapeutics
Xiaolong Wang, Can Guo, Jikuan Shao, Xinyu Zou, Shuaishuai Xing, Xu Chen, Qun Zhao, Yulan Wu, Chengliang Sun, Yao Chen, Haopeng Sun
Abstract
Traditional chemotherapeutic agents face challenges due to nonselective cytotoxicity. Targeted therapy, as an essential component of precision medicine, has achieved notable breakthroughs in recent years. The successful clinical translation of antibody-drug conjugates (ADCs) initiated the era of targeted conjugate drugs. Small molecule-drug conjugates (SMDCs), which utilize small molecules as targeting ligands, have overcome numerous limitations associated with ADCs. These agents demonstrate favorable pharmacokinetic properties, enhanced cellular penetration capabilities, and nonimmunogenicity, and exhibit significant therapeutic potential in solid tumors. This perspective provides a comprehensive overview of SMDC structures, prominent therapeutic targets, and their corresponding targeted therapies. Potential challenges associated with SMDCs, including relatively short half-life, off-target toxicity, and treatment resistance, are analyzed in depth. Furthermore, emerging design strategies for SMDCs are summarized, with the goal of expanding the conceptual framework for SMDC development and providing valuable insights for the future design of more efficient and safer SMDC therapeutics.