A First-In-Class Inhibitor of Skp1-Skp2 Interaction Has Potent Preclinical Efficacy Against Castration-Resistant Prostate Cancer
Metastatic, castration-resistant prostate cancer (mCRPC) directly contributes to the mortality and morbidity of prostate cancer. It is imperative to identify new molecular targets and discover effective therapeutic agents against lethal mCRPC. We have developed a new class of small-molecule compounds and evaluated their anticancer activities in preclinical models using molecular, cellular, and animal approaches. GH501 demonstrates nanomolar potency in the NCI-60 human cancer cell panel and multiple mCRPC cell lines with diverse genetic backgrounds, including those resistant to androgen deprivation therapy drugs. Mechanistically, GH501 may bind S-phase kinase-associated protein 1 (Skp1) and disrupt the physical interaction between Skp1 and S-phase kinase-associated protein 2 (Skp2) within the Skp1-Cullin1-F-box protein ubiquitin ligase complexes (SCF), thereby affecting multiple oncogenic signals implicated in mCRPC progression, including p21, p27, ß-catenin, cyclin D1, E2F1, enhancer of zeste homolog 2, c-Myc, and survivin. GH501 exhibits excellent in vitro and in vivo safety pharmacology, and GH501 monotherapy effectively inhibits the in vivo growth of cell- and patient-derived xenografts in intraosseous and subcutaneous models. These results indicate that GH501 is a promising therapeutic candidate for the treatment of mCRPC and warrants further preclinical development. Overall design: RNA sequencing of C4-2 prostate tumor cells treated with GH501 using Illumina TruSeq Library prep and sequenced on Illumina HiSeq 2500.