Development of HSP90 inhibitors-SN38 conjugates for cancer treatment

Yuting Cao; Qianqian Shen; Mengyuan Ding; Yi Chen; Wei Lu; Shulei Zhu

doi:10.1016/j.bioorg.2023.106582

Development of HSP90 inhibitors-SN38 conjugates for cancer treatment

Bioorg Chem. 2023 Aug:137:106582. doi: 10.1016/j.bioorg.2023.106582. Epub 2023 May 2.

Authors

Yuting Cao¹, Qianqian Shen², Mengyuan Ding¹, Yi Chen³, Wei Lu⁴, Shulei Zhu⁵

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
² Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
³ Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: ychen@simm.ac.cn.
⁴ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China. Electronic address: wlu@chem.ecnu.edu.cn.
⁵ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China. Electronic address: slzhu@chem.ecnu.edu.cn.

PMID: 37156134
DOI: 10.1016/j.bioorg.2023.106582

Abstract

Presently, chemotherapy remains to be one of the most important therapeutic approaches for malignant tumors. Ligands based drug conjugates are showing considerable promise as potential therapeutic agents delivery systems for cancer. Here, a series of HSP90 inhibitors-SN38 conjugates were developed through cleavable linkers for tumor-specific delivery of SN38 and reducing its side effects. In vitro assays showed that these conjugates exhibited acceptable stability in PBS and plasma, appreciable HSP90 binding affinity, and potent cytotoxic abilities. Cellular uptake behaviors also indicated that these conjugates could selectively target cancer cells in a time-dependent manner via HSP90. Among them, compound 10b with a glycine linkage exhibits appreciable in vitro and in vivo pharmacokinetic profiles, and excellent in vivo antitumor activity in Capan-1 xenograft models, demonstrating the selective targeting and accumulation of the active payload at tumor sites. Above all, these results suggest that compound 10b has the potential as a potent anticancer drug, meriting further evaluation in the future.

Keywords: Cancer treatment; Drug accumulation; HSP90; SN38 conjugate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Cell Line, Tumor
Humans
Neoplasms* / drug therapy

Substances

Antineoplastic Agents