10.1021/mp4004578.s001 Laura Gatti Laura Gatti Michelandrea De Cesare Michelandrea De Cesare Emilio Ciusani Emilio Ciusani Elisabetta Corna Elisabetta Corna Noemi Arrighetti Noemi Arrighetti Denis Cominetti Denis Cominetti Laura Belvisi Laura Belvisi Donatella Potenza Donatella Potenza Elisabetta Moroni Elisabetta Moroni Francesca Vasile Francesca Vasile Daniele Lecis Daniele Lecis Domenico Delia Domenico Delia Vittoria Castiglioni Vittoria Castiglioni Eugenio Scanziani Eugenio Scanziani Pierfausto Seneci Pierfausto Seneci Nadia Zaffaroni Nadia Zaffaroni Paola Perego Paola Perego Antitumor Activity of a Novel Homodimeric SMAC Mimetic in Ovarian Carcinoma American Chemical Society 2014 tumor cell resistance carcinoma cells subcutaneously xenografted novel homodimeric SMACm cell sensitivity assays SM 83 downmodulated dimeric SM 83 SM 83 Novel Homodimeric SMAC Mimetic terminal phenyl groups apoptotic cell death tumor necrosis factor novel SMACm SM 83 novel proapoptotic agents tumor volume inhibition novel treatment options TNF BIR 2 domain 2014-01-06 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Antitumor_Activity_of_a_Novel_Homodimeric_SMAC_Mimetic_in_Ovarian_Carcinoma/2335960 Treatment of ovarian carcinoma often fails to be curative because of drug resistance, and many efforts are directed to overcome tumor cell resistance by increasing apoptosis induction. The potential of second mitochondria-derived activator of caspases (SMAC) mimetics (SMACm) has appeared in preclinical studies, but novel proapoptotic agents of this class with improved pharmacological profile are needed. To identify novel treatment options for ovarian carcinoma by interfering with antiapoptotic factors, in the present study a novel homodimeric SMACm (SM83) was employed in preclinical models both in vitro and in vivo. An investigation of the structural features of dimeric SM83 as compared to a closely related reference compound indicated slight differences, likely because of the interaction between one of the terminal phenyl groups and triazole rings of SM83 with the BIR2 domain. Although SM83 per se did not inhibit cell proliferation, it displayed a synergistic effect in combination with TNF-related apoptosis inducing ligand (TRAIL) in cell sensitivity assays. Because the tumor microenvironment is a reservoir of cytokines that may act in conjunction with SMACm to affect tumor growth, the activity of the novel compound was tested in vivo in ovarian carcinoma cells subcutaneously xenografted into immunodeficient mice. A significant tumor volume inhibition was observed together with activation of caspase 3 and apoptotic cell death. A biochemical analysis of tumor necrosis factor (TNF) and TRAIL content in specimens from xenografted mice indicated that SM83 downmodulated the levels of human TNF in plasma samples and tended to upmodulate human TRAIL levels in tumors. Thus, TRAIL appears to contribute to the antitumor activity of novel SMACm SM83 in subcutaneously grown ovarian carcinoma. Overall, our results indicate that SM83 is an attractive candidate for further development.