Breast cancer is the most common malignancy in women living in the US, with more than 230,000 new cases diagnosed each year, and an estimated 40,000 women dying from the disease in 2014. Greater than 15% of these diagnoses are classified as triple negative breast cancer (TNBC), which is considered among the most aggressive breast cancer sub-types, with the worst prognosis. TNBC is difficult to treat because pharmacologic approaches are limited to systemic chemotherapies, which often fail due to high toxicity and drug resistance. Therefore, the need for highly effective therapies against TNBC is acute. We have identified a promising target for TNBC, the intracellular protein CIB1, which supports two of the most frequently activated oncogenic pathways in breast cancer-PI3K/AKT and MEK/ERK. CIB1 depletion simultaneously inhibits both pathways, profoundly killing human TNBC cells in culture and in vivo. Thus, CIB1 depletion dramatically shrinks tumors derived from a human TNBC cell line in a mouse xenograft model. These results and the fact several CIB1-depleted non-transformed cell types and CIB1 knockout mice are relatively unaffected suggest that CIB1 is a safe target. To advance CIB1 as an anti- cancer target, we formed Reveris Therapeutics LLC. In collaboration with UNC's Center for Integrative Chemical Biology and Drug Discovery directed by the PI, Dr. Stephen Frye, we identified via high throughput screening, multiple diverse chemical series of small molecule CIB1 inhibitors, and are focusing on four hit compounds. Initial testing to date indicates that these compounds enter cells, bind CIB1 and/or induce TNBC cell death with the expected properties and selectivity. Here we propose first, to initiate hit-to-lead chemistry to optimize our current hits. We will do this by establishing initia structure-activity relationships (SAR) for each identified chemical series. We will then begin iterative optimization of their properties to arrive at a lead series with sufficient potency and selectivity for further pharmacologic target validation. Leads will progress via advanced computer-aided design and medicinal chemistry. Second, we will perform biologic and pharmacokinetic evaluations. Compounds will progress through in vitro assays to cellular, ADME and in vivo pharmacokinetic and efficacy assessments to support SAR and lead series selections. We expect that completion of these aims will lead to further pre-clinical and eventually clinical studies of CIB1 targeting in TNBC.
Breast cancer (BC) is the largest cause of cancer related deaths in women worldwide. Triple negative breast cancer (TNBC) is an especially alarming form of breast cancer due to its resistance to hormone therapy and HER2-directed agents. In fact, no targeted therapy exists for TNBC. The intracellular protein, CIB1 appears to be an outstanding potential therapeutic target for several types of breast and other cancers, including TNBC. Because of the pressing need in TNBC, Reveris Therapeutics and its academic collaborators seek to accelerate hit-to-lead optimization of small molecule inhibitors of CIB1 for preclinical testing in this disease.
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| Leisner, Tina M; Freeman, Thomas C; Black, Justin L et al. (2016) CIB1: a small protein with big ambitions. FASEB J 30:2640-50 |
