A Comparative Analysis of Fibroblast Activation Protein-Targeted Small Molecule–Drug, Antibody–Drug, and Peptide–Drug Conjugates

Zana, Aureliano; Puig-Moreno, Claudia; Bocci, Matilde; Gilardoni, Ettore; Nitto, Cesare Di; Principi, Lucrezia; Ravazza, Domenico; Rotta, Giulia; Prodi, Eleonora; Luca, Roberto De; Neri, Dario; Cazzamalli, Samuele

doi:10.1021/acs.bioconjchem.3c00244

Cited by 10 publications

(3 citation statements)

References 33 publications

(62 reference statements)

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“…In a recent comparison study, an ADC (7NP2À GlyÀ ProÀ MMAE) and an SMDC (OncoFAPÀ GlyÀ ProÀ MMAE) were synthesized by using fibroblast activation protein (FAP) as the same target and employing MMAE as the same payload. [87] Their targeting specificity and therapeutic efficacy were assessed through comprehensive in vitro and in vivo experiments. Both Enzyme linked immunosorbent assay (ELISA) and Fluorescence activated Cell Sorting (FACS) results demonstrated comparable high affinity for FAP.…”

Section: Monomethyl Auristatin E (Mmae)mentioning

confidence: 99%

“…Compared to the currently available ADCs, SMDCs may exhibit considerable targeting and therapeutic efficacy. [25,87] In addition, SMDCs can not only be used for targeted treatment of cancer, but also has been applied to kidney disease and inflammation. [6] Moreover, SMDCs can be extensively utilized in the fields of imaging, [98] radiation therapy, [59] and immunotherapy.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

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Small Molecule‐Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs

Zhang,

Hu,

Aras

et al. 2024

ChemMedChem

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Conventional chemotherapy is insufficient for precise cancer treatment due to its lack of selectivity and inevitable side effects. Targeted drugs have emerged as a promising solution for precise cancer treatment. A common strategy is to conjugate therapeutic agents with ligands that can specifically bind to tumor cells, providing targeted therapy. Similar to the more successful antibody drug conjugates (ADCs), small molecule drug conjugates (SMDCs) are another promising class of targeted drugs, consisting of three parts: targeting ligand, cleavable linker and payload. Compared to ADCs, SMDCs have the advantages of smaller size, better permeability, simpler preparation process and non‐immunogenicity, making them a promising alternative to ADCs. This review describes the characteristics of the targeting ligand, linker and payload of SMDCs and the criteria for selecting a suitable one. We also discuss recently reported SMDCs and list some successful SMDCs that have entered clinical trials.

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Section: Monomethyl Auristatin E (Mmae)mentioning

confidence: 99%

Section: Conclusion and Perspectivementioning

confidence: 99%

Small Molecule‐Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs

Zhang,

Hu,

Aras

et al. 2024

ChemMedChem

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show abstract

“…Furthermore, Zana compared the in vitro and in vivo properties of fibroblast activation protein (FAP)-targeted ADCs, PDCs, and SMDCs equipped with “Gly-Pro-MMAE”, a novel FAP-cleavable linker-payload for the selective release of MMAE in tumor lesions. Comparison of the efficacy of different conjugates at the same dose showed that SMDC was superior to non-targeted protein conjugates in tumor targeted therapy …”

Section: Introductionmentioning

confidence: 99%

Small Molecule–Drug Conjugates Emerge as a New Promising Approach for Cancer Treatment

Wang,

Li,

Wei

et al. 2024

Mol. Pharmaceutics

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Antibody drug conjugates (ADCs) have emerged as a new promising class of anti-cancer agents. However, limitations such as higher costs and unavoidable immunogenicity due to their relatively large structures cannot be ignored. Therefore, the development of lightweight drugs such as small molecule−drug conjugates (SMDCs) based on the ADC design idea has become a new option for targeted therapy. SMDCs are derived from the coupling of small-molecule targeting ligands with cytotoxic drugs. They are composed of three parts: small-molecule targeting ligands, cytotoxic molecules, and linkers. Compared with ADCs, SMDCs can be more rapidly and evenly dispersed into tumor tissues, with low cost and no immunogenicity. In this article, we will give a comprehensive review of different types of SMDCs currently under clinical trials to provide ideas and inspirations for the development of clinically applicable SMDCs.

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Amine‐Carbamate Self‐Immolative Spacers Counterintuitively Release 3° Alcohol at Much Faster Rates than 1° Alcohol Payloads

Mason,

Bisbal Lopez,

Bashiri

et al. 2024

ChemBioChem

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Self‐immolative (SI) spacers are degradable chemical connectors widely used in prodrugs and drug conjugates to release pharmaceutical ingredients in response to specific stimuli. Amine‐carbamate SI spacers are particularly versatile, as they have been used to release different hydroxy cargos, ranging from 2° and 3° alcohols to phenols and oximes. In this work, we describe the ability of three amine‐carbamate SI spacers to release three structurally similar imidazoquinoline payloads, bearing either a 1°, a 2° or a 3° alcohol as the leaving group. While the spacers showed comparable efficacy at releasing the 2° and 3° alcohols, the liberation of the 1° alcohol was much slower, unveiling a counterintuitive trend in nucleophilic acyl substitutions. The release of the 1° alcohol payload was only possible using a SI spacer bearing a pyrrolidine ring and a tertiary amine handle, which opens the way to future applications in drug delivery systems.

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A Comparative Analysis of Fibroblast Activation Protein-Targeted Small Molecule–Drug, Antibody–Drug, and Peptide–Drug Conjugates

Cited by 10 publications

References 33 publications

Small Molecule‐Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs

Small Molecule‐Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs

Small Molecule–Drug Conjugates Emerge as a New Promising Approach for Cancer Treatment

Amine‐Carbamate Self‐Immolative Spacers Counterintuitively Release 3° Alcohol at Much Faster Rates than 1° Alcohol Payloads

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