Carmen Ramos*1, Gloria Crespo 1, Nuria de Pedro 1, Carmen Griñán-Lisón 2, Caridad Díaz 1, Víctor González-Menéndez 1, Juan A. Marchal 2, Rosario Fernández-Godino 1, Olga Genilloud 1 and Fernando Reyes 1.

1Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento 34, 18016 Granada, Spain.

Biosanitary Research Institute of Granada (ibs. GRANADA), University Hospitals of Granada-University of Granada, Granada, Spain.

Pancreatic cancer shows a high fatality rate that can only be faced with a combination of surgery and post-surgical chemotherapy. Unfortunately, advanced patients can only hope for palliative treatment, which raises an important need for the identification of chemotherapeutic agents that improve the quality of life. In this study, we have identified and isolated six new benzophenone derivatives, onychocolones A-F with antitumoral activity. The compounds were obtained from an anti-tumor high throughput screening followed by bioassay-guided fractionation of extracts of the strain CF-107644 of the fungus Onychocola sp., isolated from a soil sample in Spain. The structures of the new compounds were established by spectroscopic methods, including ESI-TOF MS and 1D and 2D NMR analyses, X-ray diffraction, and comparison with previously reported data for similar structures. Four compounds significantly inhibited the growth of the MIA PaCa-2, BxPC-3, and PANC-1 pancreatic cancer cell lines, with low-micromolar Median Effective Dose (ED50s). Onychocolone A was prioritized for further profiling, due to its pro-apoptotic effect. Onychocolone A showed a cytotoxic effect on 3D spheroids and cancer stem cells (CSC) derived from pancreatic cell lines, which was mechanistically linked to the inhibition of the MEK onco-signaling pathway. The in vivo efficacy of Onychocolone A was demonstrated by the reduction of tumor growth in a heterotopic pancreatic xenograft mice model generated by CSC. The ADME-tox profile of this compound was also validated in vitro and in vivo. Altogether, the data support that Onychocolone A is a promising new small molecule for hit-to-lead phase for the development of a new treatment of pancreatic cancer.