Re-Evaluating\nPIN1 as a Therapeutic Target in Oncology\nUsing Neutral Inhibitors and PROTACs

Peptidyl-prolyl cis–trans isomerase NIMA-interacting\n1 (PIN1)\nhas emerged as a promising therapeutic target for cancer treatment.\nHowever, the current PIN1 inhibitors have shown limited efficacy in\nanimal models, leaving the question of whether PIN1 is a proper oncologic\ntarget still unanswered. By screening a 1 trillion DNA-encoded library\n(DEL), we identified novel nonacidic compounds. Among resynthesized\nDEL compounds, <b>DEL1067</b>-<b>56</b>-<b>469</b> (<b>A0</b>) is the most potent one (KD = 430 nM, IC<sub>50</sub> = 420 nM). Further optimization of <b>A0</b> resulted in compound <b>C10</b> with much improved potency (KD = 25 nM, IC<sub>50</sub> = 150 nM). As an alternative approach, <b>C10</b> was then\nconverted into proteolysis targeting chimeras (PROTACs) in order to\nachieve deeper downregulation of the PIN1 protein in cancer cell lines.\nUnfortunately, neither PIN1 inhibitors nor PIN1 PROTACs demonstrated\nmeaningful antiproliferation activity. In addition, siRNA knock-down\nexperiments provided unfavorable evidence of PIN1 as an oncologic\ntarget. Our findings highlight the complexity of targeting PIN1 for\ncancer therapy.