Homo sapiens Riok2 (HsRiok2) is an atypical, Ser/Thr protein kinase that has been implicated in a number of cancers, including Prostate Cancer. More recently, evidence has shown that HsRiok2 plays a biological role in the upregulation of ERG-positive cancer cells, thus presenting itself as an attractive drug target. The first known prostate cancer inhibitor against HsRiok2 has been identified, as well as select derivative inhibitors and has been shown both in vitro and in vivo to target HsRiok2. Here, the first ever Homo sapiens Riok2 in complex with two known Prostate Cancer inhibitors at 1.75 Å resolution and 2.70 Å resolution is reported, respectively. To evaluate conformational changes upon inhibitor binding, the first ever Homo sapiens Riok2 transition state complex is reported, capturing a snapshot of the kinase poised for phosphoryl transfer, at 2.80 Å resolution. These structural insights reveal the influence of the phosphate-binding loop (P-loop) in HsRiok2’s dimerization and potentially a catalytically inactive state, mediated by the presence of the drug candidate. Its dimerization interface is prevented from interacting with the Pre-40S ribosome, preventing HsRiok2 from carrying out its function as an ATPase/Kinase to further mature the pre-40S particle. These findings provide the first blueprint for a structure-based drug design approach to facilitate the development of more selective prostate cancer inhibitors.