Program

OR35-1

CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has Therapeutic Effect on HPV-Induced Neoplasia

[Speaker] Masahiko Ajiro:1
[Co-author] Hiroyuki Sakai:2, Hiroshi Onogi:3, Takashi Nomura:4, Kenji Kabashima:4, Masatoshi Hagiwara:1,5
1:Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Japan, 2:Laboratory of Tumor Viruses, Institute for Frontier Life and Medical Sciences, Kyoto University, Japan, 3:KinoPharma Inc., Japan, 4:Department of Dermatology, Kyoto University Graduate School of Medicine, Japan, 5:Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Japan

Background: Cervical cancer is one of the leading cause of cancer deaths among women worldwide, and human papillomavirus (HPV) infection is the etiology in more than 95% of cases. HPV induces tumorigenesis through viral oncogenes E6 and E7, which depend on host cell factor cyclin-dependent kinase 9 (CDK9) for their transcriptional activation. In this study, we assessed the availability of newly developed CDK9 inhibitor FIT-039 for therapy against cervical malignancy by targeting HPV viral gene expression and replication.
Methods: We examined FIT-039 for HPV viral gene expression in HPV+ cervical cancer cells. Primary keratinocytes monolayer and organotypic raft culture models were used to evaluate HPV viral replication and cervical intraepithelial neoplasia (CIN) phenotypes. Preclinical assessment of FIT-039 was further conducted for pharmacodynamics and safety tests. Anti-HPV effect of FIT-039 was further examined in vivo, using HPV+ cervical cancer xenografts.
Results: FIT-039 inhibits HPV replication and expression of E6 and E7 viral oncogenes, restoring tumor suppressors, p53 and pRb in HPV+ cervical cancer cells. The therapeutic effect of FIT-039 was demonstrated in CIN model of an organotypic raft culture, where FIT-039 suppressed HPV18-induced dysplasia/hyperproliferation with reduction in viral load. FIT-039 also repressed HPV16+ but not HPV- cervical cancer xenografts without any significant adverse effects. Safety and pharmacokinetics of FIT-039 were confirmed for systemic and topical routes.
Conclusions: CDK9 inhibitor FIT-039 showed potent anti-HPV activity without significant toxicity in preclinical studies. Thus, FIT-039 is expected to be novel therapeutics for CIN by targeting HPV. FIT-039 is currently evaluated in the phase I/IIa trial for HPV-induced common wart, and further prospective is its application for CIN treatment.

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