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Small molecule-drug conjugates: A novel strategy for cancer-targeted treatment
Chunlin Zhuang1, Xianghong Guan2, Hao Ma1
1School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China; School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
Abstract:
Targeted therapy has become an effective strategy of precision medicine for improving cancer treatment. Selectivity improvement is always popular in modern oncology because of decreased side effects in conventional cancer chemotherapy. The use of antibody-drug conjugates (ADC), a robust strategy for targeted therapy, applies antibodies to selectively deliver a potent cytotoxic compound to tumor cells and thus improve the therapeutic efficacy of the chemotherapeutic agents. Three ADC products (trastuzumab emtansine, brentuximab vedotin and inotuzumab ozogamicin) are already on the market, and several compounds are in clinical trials. Compared with ADCs, small molecule-drug conjugates (SMDCs) provide a new, less established perspective for targeted delivery. Nevertheless, SMDCs have several strengths: they have 1) a non-immunogenic nature, 2) much more manageable synthesis, 3) lower molecular weights, which confer a high potential for good cell penetration in solid tumors. SMDCs might therefore be a promising alternative with similar efficacy to ADCs. In this article, we highlight the medicinal chemistry aspects of SMDC design. SMDC targeting ligands, linkers and small-molecule payloads will be discussed. Successful cases of SMDCs used as therapeutic agents and other applications of SMDC will also be included.
Insights
Small molecule-drug conjugates (SMDCs) offer a promising targeted therapy alternative to antibody-drug conjugates (ADCs) for cancer treatment. SMDCs present advantages like non-immunogenicity and better tumor penetration, potentially matching ADC efficacy with fewer side effects.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Delivery Systems
Background:
- Targeted therapy, a cornerstone of precision medicine, aims to enhance cancer treatment efficacy while minimizing side effects.
- Antibody-drug conjugates (ADCs) represent a successful targeted therapy strategy, delivering cytotoxic payloads selectively to tumor cells.
- Existing ADCs include trastuzumab emtansine, brentuximab vedotin, and inotuzumab ozogamicin, with more in clinical development.
Purpose of the Study:
- To explore small molecule-drug conjugates (SMDCs) as a novel and potentially advantageous targeted drug delivery system.
- To highlight the medicinal chemistry principles involved in designing effective SMDCs.
- To discuss the potential of SMDCs as a viable alternative to ADCs in cancer therapy.
Main Methods:
- Review of medicinal chemistry aspects in SMDC design, focusing on targeting ligands, linkers, and payloads.
- Analysis of the inherent strengths of SMDCs, including non-immunogenicity, synthetic manageability, and favorable molecular weight for tumor penetration.
- Examination of successful SMDC applications and their therapeutic potential.
Main Results:
- SMDCs offer a less established but promising approach to targeted cancer therapy.
- Key advantages of SMDCs include their non-immunogenic nature, simpler synthesis, and lower molecular weight, facilitating better penetration into solid tumors.
- These characteristics suggest SMDCs could achieve efficacy comparable to ADCs.
Conclusions:
- Small molecule-drug conjugates (SMDCs) represent a promising frontier in targeted cancer therapy, offering distinct advantages over antibody-drug conjugates (ADCs).
- The medicinal chemistry of SMDC design, encompassing ligands, linkers, and payloads, is crucial for optimizing their therapeutic potential.
- SMDCs hold significant promise as effective and potentially safer alternatives for cancer treatment, warranting further investigation and development.
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