Abstract A09: SM08502, a novel, small-molecule CDC-like kinase (CLK) inhibitor, demonstrates strong inhibition of the Wnt signaling pathway and antitumor effects in diverse ovarian cancer models

Aberrant activation of the Wnt signaling pathway is observed in ovarian cancer (OC) and is associated with chemoresistance, immune evasion, and poor prognosis. SM08502 is a novel, oral, small-molecule pan-CLK inhibitor that has been shown to potently inhibit the Wnt signaling pathway in preclinical colorectal cancer models. The purpose of these studies was to test the in vitro and in vivo activity of SM08502 in preclinical models of OC. The effect of SM08502 on cell viability was tested in 10 OC cell lines of various histotypes, including high-grade serous (HGS), serous, endometrioid, clear-cell, and teratocarcinoma lines in vitro. Cell proliferation was impaired in all cell lines by SM08502 regardless of histotype and mutation profile (average EC50=0.123 μM [0.034 – 0.275]). Relative to DMSO, SM08502 (1 μM) also potently inhibited Wnt-related gene expression (TCF7, DVL2, LRP5, and ERBB2), which correlated with inhibition of protein expression in HGSOC, endometrioid, and teratocarcinoma cell lines. Additionally, in cell lines derived from these histotypes, SM08502 strongly inhibited cyclin E1 gene and protein expression, the amplification/overexpression of which has been associated with treatment resistance and poor overall survival in HGSOC. In vivo antitumor effects and tolerability of oral SM08502 (6.25, 12.5 and 25 mg/kg QD for 15-22 days) were assessed in mice bearing OVCAR-3 (HGSOC; TP53mut), PA-1 (teratocarcinoma; N-Ras mut), and TOV-112D (endometrioid; CTNNB1mut) xenografts (n=5 mice per group). In OVCAR-3 xenografts, significant tumor growth inhibition (TGI) vs. vehicle occurred in mice treated with SM08502 12.5 mg/kg (66%, p