2. Academic Validation
  3. The novel drug candidate S2/IAPinh improves survival in models of pancreatic and ovarian cancer

The novel drug candidate S2/IAPinh improves survival in models of pancreatic and ovarian cancer

  • Sci Rep. 2024 Mar 16;14(1):6373. doi: 10.1038/s41598-024-56928-z.
Takaomi Hagi 1,  Suwanna Vangveravong 1,  Rony Takchi 1,  Qingqing Gong 1,  S Peter Goedegebuure 1 2,  Herve Tiriac 3,  Brian A Van Tine 2 4,  Matthew A Powell 2 5,  William G Hawkins 6 7,  Dirk Spitzer 8 9
Affiliations

Affiliations

  • 1 Department of Surgery, Washington University School of Medicine, S. Euclid Avenue, St. Louis, MO, 63110, USA.
  • 2 Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA.
  • 3 Division of Surgical Oncology, Department of Surgery, Moores Cancer Center, University of California San Diego, San Diego, CA, USA, San Diego, USA.
  • 4 Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA.
  • 5 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA.
  • 6 Department of Surgery, Washington University School of Medicine, S. Euclid Avenue, St. Louis, MO, 63110, USA. hawkinwi@musc.edu.
  • 7 Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA. hawkinwi@musc.edu.
  • 8 Department of Surgery, Washington University School of Medicine, S. Euclid Avenue, St. Louis, MO, 63110, USA. spitzerd@musc.edu.
  • 9 Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA. spitzerd@musc.edu.
PMID: 38493257 DOI: 10.1038/s41598-024-56928-z
Abstract

Cancer selective Apoptosis remains a therapeutic challenge and off-target toxicity has limited enthusiasm for this target clinically. Sigma-2 ligands (S2) have been shown to enhance the Cancer selectivity of small molecule drug candidates by improving internalization. Here, we report the synthesis of a novel drug conjugate, which was created by linking a clinically underperforming SMAC mimetic (second mitochondria-derived activator of caspases; LCL161), an inhibitor (antagonist) of inhibitor of Apoptosis proteins (IAPinh) with the sigma-2 ligand SW43, resulting in the new chemical entity S2/IAPinh. Drug potency was assessed via cell viability assays across several pancreatic and ovarian Cancer cell lines in comparison with the individual components (S2 and IAPinh) as well as their equimolar mixtures (S2 + IAPinh) both in vitro and in preclinical models of pancreatic and ovarian Cancer. Mechanistic studies of S2/IAPinh-mediated cell death were investigated in vitro and in vivo using syngeneic and xenograft mouse models of murine pancreatic and human ovarian Cancer, respectively. S2/IAPinh demonstrated markedly improved pharmacological activity in Cancer cell lines and primary Organoid cultures when compared to the controls. In vivo testing demonstrated a marked reduction in tumor growth rates and increased survival rates when compared to the respective control groups. The predicted mechanism of action of S2/IAPinh was confirmed through assessment of Apoptosis pathways and demonstrated strong target degradation (cellular inhibitor of Apoptosis proteins-1 [cIAP-1]) and activation of caspases 3 and 8. Taken together, S2/IAPinh demonstrated efficacy in models of pancreatic and ovarian Cancer, two challenging malignancies in need of novel treatment concepts. Our data support an in-depth investigation into utilizing S2/IAPinh for the treatment of Cancer.

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