Abstract 4539: NMS-P862, a novel orally available selective small molecule Cdc7 inhibitor with antitumor efficacy in breast cancer

Abstract

Abstract Cdc7 is an essential serine/threonine protein kinase that licenses initiation of DNA synthesis at replication origins, promotes cell cycle checkpoint activation in response to replication stress and is involved in additional aspects of DNA metabolism, including repair mechanisms. Cdc7 is therefore a potential target for cancer therapy, with a distinct mechanism of action from known drugs that inhibit DNA replication. Overexpression of Cdc7 is found in various types of cancer, suggesting that its deregulated activity may promote survival of cancer cells, as well as tumor progression. In particular, its overexpression in breast cancer is linked to triple negative, HER2 positive subtypes, genomic instability, arrested tumor differentiation and enhanced survival. Depletion through RNA silencing, or inhibition of the kinase activity of Cdc7 induces S-phase arrest and apoptosis in cancer cell lines, while non-transformed epithelial cells arrest in G1, remain viable, and are able to resume cell proliferation on recovery of Cdc7 activity. We have previously reported the identification of NMS-P354, an orally bioavailable Cdc7 inhibitor which promotes tumor growth inhibition in preclinical cancer models and was very helpful in validating Cdc7 as potential target. Here, we describe the characterization of NMS-P862, a follow -on, novel, potent (IC50: 9 nM) and more selective Cdc7 inhibitor. Profiling of anti-proliferative activity against more than one hundred human tumor cell lines indicated relatively high activity (IC50< 0.5 μM) against triple negative or HER2 positive/double negative breast cancer lines, as well as against prostate cancer cell lines. In vivo, oral administration of NMS-P862 resulted in dose-dependent antitumor activity, including for example tumor regression in a carcinogen (7,12-dimethylbenz[α]antracene) induced rat breast cancer model, for which we observed 9/12 objective responses, assessed as per RECIST criteria. A favorable ADME profile with high oral bioavailability, together with permissive therapeutic safety margins in test species at efficacious exposures, indicate that NMS-P862 is suitable for further development, affording the possibility to target cancer via a novel mechanism which we believe is suited to both single agent and opportune drug combination approaches. Citation Format: Alessia Montagnoli, Maria Menichincheri, Nadia Amboldi, Dario Ballinari, Marina Ciomei, Francesco Fiorentini, Rosita Lupi, Daniele Pezzetta, Sonia Rainoldi, Daniele Pezzetta, Eduard Felder, Antonella Isacchi, Enrico Pesenti, Arturo Galvani. NMS-P862, a novel orally available selective small molecule Cdc7 inhibitor with antitumor efficacy in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4539. doi:10.1158/1538-7445.AM2014-4539