{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:18:00Z","timestamp":1788369480349,"version":"build-2803163510"},"reference-count":293,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Defense Prostate Cancer Research Program Idea Development Award","award":["PC150431 GRANT11996600"],"award-info":[{"award-number":["PC150431 GRANT11996600"]}]},{"name":"Department of Defense Prostate Cancer Research Program Idea Development Award","award":["UL1TR002378"],"award-info":[{"award-number":["UL1TR002378"]}]},{"DOI":"10.13039\/100006108","name":"NCATS","doi-asserted-by":"publisher","award":["PC150431 GRANT11996600"],"award-info":[{"award-number":["PC150431 GRANT11996600"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"NCATS","doi-asserted-by":"publisher","award":["UL1TR002378"],"award-info":[{"award-number":["UL1TR002378"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Metastatic prostate cancer (mPCa) has limited therapeutic options and a high mortality rate. The p21-activated kinase (PAK) family of proteins is important in cell survival, proliferation, and motility in physiology, and pathologies such as infectious, inflammatory, vascular, and neurological diseases as well as cancers. Group-I PAKs (PAK1, PAK2, and PAK3) are involved in the regulation of actin dynamics and thus are integral for cell morphology, adhesion to the extracellular matrix, and cell motility. They also play prominent roles in cell survival and proliferation. These properties make group-I PAKs a potentially important target for cancer therapy. In contrast to normal prostate and prostatic epithelial cells, group-I PAKs are highly expressed in mPCA and PCa tissue. Importantly, the expression of group-I PAKs is proportional to the Gleason score of the patients. While several compounds have been identified that target group-I PAKs and these are active in cells and mice, and while some inhibitors have entered human trials, as of yet, none have been FDA-approved. Probable reasons for this lack of translation include issues related to selectivity, specificity, stability, and efficacy resulting in side effects and\/or lack of efficacy. In the current review, we describe the pathophysiology and current treatment guidelines of PCa, present group-I PAKs as a potential druggable target to treat mPCa patients, and discuss the various ATP-competitive and allosteric inhibitors of PAKs. We also discuss the development and testing of a nanotechnology-based therapeutic formulation of group-I PAK inhibitors and its significant potential advantages as a novel, selective, stable, and efficacious mPCa therapeutic over other PCa therapeutics in the pipeline.<\/jats:p>","DOI":"10.3390\/cancers15082236","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T03:11:23Z","timestamp":1681182683000},"page":"2236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Targeting P21-Activated Kinase-1 for Metastatic Prostate Cancer"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3017-0230","authenticated-orcid":false,"given":"Payaningal R.","family":"Somanath","sequence":"first","affiliation":[{"name":"Department of Clinical & Administrative Pharmacy, College of Pharmacy, University of Georgia, Augusta, GA 30912, USA"},{"name":"MetasTx LLC, Basking Ridge, NJ 07920, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Chernoff","sequence":"additional","affiliation":[{"name":"MetasTx LLC, Basking Ridge, NJ 07920, USA"},{"name":"Fox Chase Cancer Center, Philadelphia, PA 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian S.","family":"Cummings","sequence":"additional","affiliation":[{"name":"MetasTx LLC, Basking Ridge, NJ 07920, USA"},{"name":"Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandip M.","family":"Prasad","sequence":"additional","affiliation":[{"name":"Morristown Medical Center, Atlantic Health System, Morristown, NJ 07960, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5435-9727","authenticated-orcid":false,"given":"Harvey D.","family":"Homan","sequence":"additional","affiliation":[{"name":"MetasTx LLC, Basking Ridge, NJ 07920, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1177\/1557988318798279","article-title":"Global Trends and Prostate Cancer: A Review of Incidence, Detection, and Mortality as Influenced by Race, Ethnicity, and Geographic Location","volume":"12","author":"Taitt","year":"2018","journal-title":"Am. 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