Characterization of novel pyrazole compounds with potent anti-cancer activity

Breast cancer is the most frequently diagnosed tumor type and a common cause of cancer-related deaths in women worldwide. In the US, Triple Negative Breast Cancer (TNBC) continues to be a deadly disease. Since TNBC is an aggressive subtype with no available molecular targets and lack of immunotherapy, we have focused our recent drug screens to identify compounds that are cytotoxic against these cells. Using a live- cell imaging screening assay developed by my group, we recently screened 4,600 novel compounds from the Chembridge DIVERset drug-like library of compounds on the MDA- MB-231 TNBC line and detected fifteen compounds with significant cytotoxic activity against these cells. The most potent of the compounds (a pyrazole-3-carbohydrazyde named P3C) was subsequently evaluated on additional cancer cell lines and found to be cytotoxic to most cancer cell lines. A recent search for structural analogues of P3C resulted in the identification of a compound (P3C.1) with stronger anti-cancer activity than the original. Although P3C and P3C.1 have similar cytotoxic activity on a variety of cancer cell lines, they also differ in activity on a small subset of cell lines. Our data indicate that they both induce apoptosis via increased reactive oxygen species, mitochondrial depolarization, caspase activation, cell membrane disruption, and DNA fragmentation. However, our preliminary results indicate that the pyrazoles activate distinct signal transduction pathways. Our central hypothesis is that the identified pyrazoles induce apoptosis via distinct pathways. Therefore, the main objective of this project is to determine the mode of action (MOA) of each compound by comparing their gene expression profiles and effects on key signal transduction pathways.
Understanding the MOA of these compounds is critical when testing compounds in clinical trials and in drug combination therapy. In addition, an important goal of this proposal is to determine if the compounds reduce/inhibit tumor progression in mice implanted with human tumors with the hope of eventually translating this basic research into effective anticancer therapeutics that can help reduce mortality in cancer patients.

Grant Number: 5R16GM149379-04
NIH Institute/Center: NIH
Principal Investigator: RENATO AGUILERA