Thursday, April 25, 2024
4/25/2024
Abstract Skp2, an F-box protein that constitutes one of the four subunits of the SCF ubiquitin E3 ligase complex, regulates cell-cycle progression by targeting ubiquitination and degradation of its substrates, such as the cell-cycle inhibitor p27. Skp2 E3 ligase has a broad implication in cancer, especially for androgen-independent human metastatic prostate cancer. We showed that Skp2 expression was upregulated in metastatic prostate cancer specimens and castration-resistant prostate cancer (CRPC) and correlated with Myc expression. We further demonstrated that Skp2 is a novel E3 ligase for Akt that triggers nonproteolytic K63-linked ubiquitination of Akt, facilitating growth factor-mediated Akt membrane recruitment and activation. All together suggest that Skp2 simultaneously regulates Akt signaling and p27 degradation, and TWIST-mediated EMT to promote CRPC progression and resistance to androgen deprivation therapy (ABT). Although Skp2 SCF complex E3 ligase is a highly validated drug target for cancer, due to the lack of an effective protein-protein interaction inhibitors, Skp2 SCF complex E3 ligase is still considered as non-drugable. The proteolysis targeting chimera (PROTAC) approach could increase potency of non-drugable inhibitors due to its catalytic degradation. In this proposal, we have discovered a potent Skp2 PRO-1 by improving therapeutic window more than 100 fold in vitro over small molecule inhibitors. Skp2-PRO-1 can completely degrade Skp2 with 100 nM concentration in cancer cells and demonstrate the complete in vivo Skp2 degradation and robust antitumor efficacy in challenging and advanced CRPC tumor models including the genetic CRPC mouse model with intact immunity. To obtain two clinical candidates, we will evaluate the PK properties of Skp2-PRO-1, a Cereblon based PROTAC and improve its PK and drug properties as the first clincial candidate. We will further develop a VHL/or MDM2 based Skp2 PROTAC as the back-up candidate. Finally we will validate the clinical candidates in advanced CRPC in vivo models using diverse xenograft modes, cancer organoids, patient-derived xenografts (PDXs) and genetic mouse models. The resulted clinical candidates will be advanced into the IND enabling studies for the phase I clinical trials for the treatment of cancer.
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