Development of a PAK4-targeting PROTAC for renal carcinoma therapy: concurrent inhibition of cancer cell proliferation and enhancement of immune cell responseResearch in context
Shan Xu,
Bohan Ma,
Yanlin Jian,
Chen Yao,
Zixi Wang,
Yizeng Fan,
Jian Ma,
Yule Chen,
Xiaoyu Feng,
Jiale An,
Jiani Chen,
Ke Wang,
Hongjun Xie,
Yang Gao,
Lei Li
Affiliations
Shan Xu
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Bohan Ma
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Yanlin Jian
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Chen Yao
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Zixi Wang
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Yizeng Fan
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Jian Ma
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Yule Chen
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Xiaoyu Feng
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Jiale An
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Jiani Chen
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Ke Wang
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Hongjun Xie
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Yang Gao
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China
Lei Li
Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, China; Corresponding author. #277 Yanta West Road, Shaanxi 710061, China.
Summary: Background: Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment. Methods: Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader). Findings: We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation in vitro and in vivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application. Interpretation: This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer. Funding: This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.
