Abstract Background: High Grade Serous Ovarian Carcinoma (HGSOC) is especially lethal due to frequent diagnosis at advanced stage and development of chemoresistance. The oncogenic transcription factors C-terminal binding proteins 1 and 2 (CtBP1/2; or “CtBP”) are transcriptional scaffolds/coregulators that drive tumor progression and metastasis in many solid tumors and are amplified in ∼10% of HGSOC, with their frequent protein overexpression correlated with poor prognosis. Results: We have previously reported that CtBP transcriptionally represses the proapoptotic Death Receptors (DR) 4/5 in HGSOC cells, preventing activation of caspase 8-dependent apoptosis. Aside from its role as an oncogenic dependency in HGSOC, CtBP is a therapeutic target encoding an NAD-dependent dehydrogenase domain against which we have developed small molecule CtBP inhibitors (CtBPi) which exhibit significant anti-tumor activity in various solid tumor models without toxicity. Our current lead CtBPi’s, NAS-2-133/134, which are naphthyl derivatives of the 1st generation CtBP inhibitor scaffold 2-hydroxyimino-3-phenylpropanoic acid, exhibit IC50 values of 4-17 µM in multiple HGSOC cell lines, while A2780 cells with homozygous deletion of CtBP1/2 (A2780/DKO) were resistant to NAS-2-134 relative to parental A2780 cells (IC50s = 25 µM beyond titration vs. 20 µM, respectively), demonstrating that NAS-2-134 exhibits potent on target cytotoxic selectivity. In addition, NAS-2-134 induced caspase-8 dependent apoptosis in HGSOC cells via upregulation of DR5 and exhibited synergistic cytotoxicity when combined with the DR5 agonists MD5.1 or Biomyifi using Bliss methodology (Bliss synergy scores: MD5.1=15.8, BIOYMIFI=15.3). Further mechanistic studies revealed NAS-2-134 decreased Bcl-2 levels, which prompted evaluation of potential synergy of NAS-2-134 with BH3-mimetics venetoclax (ABT-199) and navitoclax (ABT-263), which target Bcl-2 and Bcl-2/XL, respectively. Though NAS-2-134 and ABT-199 did not exhibit synergistic cell killing in HGSOC cells, NAS-2-134 and ABT-263 exhibited strong synergy with a Bliss score of 47. Importantly, both NAS-2-134 and the closely related CtBPi NAS-2-133 demonstrated potent in vivo antitumor activity, abrogating growth of OVCAR3 xenografts in immune deficient mice. Conclusion: We demonstrate that NAS-2-134 exhibits target selective cytotoxicity in HGSOC cells via induction of caspase-8/DR5 dependent apoptosis in vitro and both NAS-2-134 and NAS-2-133 exhibit potent anti-HGSOC tumor activity in vivo; and 2) concerted targeting of CtBP and DR5 or Bcl-2/XL is synergistically cytotoxic in HGSOC cells and this strategy may lead to a future low toxicity precision therapy for chemoresistant HGSOC. Citation Format: Kranthi Kumar Chougoni, Nicholette St. Martin, Diana T. Dcona, Nari Kim, Boxiao Ding, Ronny I. Drapkin, Keith C. Ellis, Steven R. Grossman. Synergistic combinations of novel small molecule CtBP inhibitors with DR5 agonists or BH3-mimetic PROTACs targeting chemoresistant high grade serous ovarian carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3064.
Chougoni et al. (Fri,) studied this question.