{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T04:47:26Z","timestamp":1785646046308,"version":"3.56.0"},"reference-count":29,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82071558"],"award-info":[{"award-number":["82071558"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82141109"],"award-info":[{"award-number":["82141109"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82071558"],"award-info":[{"award-number":["82071558"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82141109"],"award-info":[{"award-number":["82141109"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009592","name":"Beijing Municipal Science & Technology Commission","doi-asserted-by":"crossref","award":["Z241100009024044"],"award-info":[{"award-number":["Z241100009024044"]}],"id":[{"id":"10.13039\/501100009592","id-type":"DOI","asserted-by":"crossref"}]},{"award":["Z241100009024044"],"award-info":[{"award-number":["Z241100009024044"]}],"id":[{"id":"https:\/\/ror.org\/034k14f91","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Pituitary neuroendocrine tumors (PitNETs) frequently exhibit invasive behaviors that complicate clinical treatment. While cyclin-dependent kinase 5 (CDK5) and lymphokine-activated killer T-cell-originated protein kinase (PBK, also known as PDZ-binding kinase) are implicated in tumor progression, their reciprocal regulatory mechanism remains unclear. This study aims to elucidate the CDK5-PBK interaction in PitNETs and identify potential therapeutic agents targeting this pathway. Methods: We utilized proximity labeling and phospho-specific assays to characterize the CDK5 and PBK interaction in PitNET cell lines. Immunohistochemical analysis was performed on patient tumor tissues to evaluate clinical relevance. Artificial intelligence (AI)-based virtual screening was employed to discover dual-target inhibitors. The therapeutic efficacy of the identified compound, proguanil hydrochloride, was subsequently evaluated using in vitro functional assays, alongside in vivo xenograft animal models. Results: We identified a mutual phosphorylation loop between CDK5 (at S159) and PBK (at T9) that activates insulin signaling, thereby promoting cellular proliferation and invasion in PitNETs. Patient tumor analysis revealed that the co-expression of phosphorylated CDK5 (S159) and PBK (T9) significantly correlates with tumor invasiveness (p &lt; 0.001). Through AI screening, proguanil hydrochloride was identified as a candidate dual-target inhibitor. In vitro assays confirmed that it effectively reduces tumor cell growth, while in vivo xenograft studies validated its capacity to inhibit tumor progression. Conclusions: The CDK5-PBK mutual phosphorylation axis serves as a key driver of invasiveness in PitNETs. Proguanil hydrochloride represents a promising candidate dual-target therapeutic agent capable of disrupting this pathway to suppress tumor growth.<\/jats:p>","DOI":"10.3390\/genes17080909","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T15:02:01Z","timestamp":1785510121000},"page":"909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual-Target Inhibition of CDK5 and PBK in Pituitary Neuroendocrine Tumors: Mechanisms and Therapeutic Potential"],"prefix":"10.3390","volume":"17","author":[{"given":"Jinghao","family":"Jin","sequence":"first","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyi","family":"Yi","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Gong","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazhuo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyan","family":"Xie","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1001\/jama.2023.5444","article-title":"Diagnosis and Management of Pituitary Adenomas: A Review","volume":"329","author":"Tritos","year":"2023","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3171\/2024.11.JNS242484","article-title":"Indications and outcomes of the extended endoscopic endonasal approach for the removal of \u201cunconventional\u201d suprasellar pituitary neuroendocrine tumors","volume":"143","author":"Solari","year":"2025","journal-title":"J. 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