Small Inhibitors Against Lipocalin-2 for Inflammatory Breast Cancer Treatment and Associated Diseases

Puerto Rico Science, Technology & Research Trust Background
Inflammatory breast cancer (IBC) is a highly metastatic and very aggressive form of primary breast cancer that disproportionally affects younger women. Even though it is considered rare (2-4% of all breast cancer cases in the US), IBC results in a high mortality rate of 7-10% of breast cancer-related deaths, having a five-year survival rate of only 40%. Despite its aggressiveness, there is still no specific targeted therapies for IBC due to the lack of a clear understanding of the particular cellular and molecular mechanisms that drive IBC development and aggressive behavior.
Technology Overview
Lipocalin-2 (LCN2), also known as NGAL (neutrophil gelatinase-associated Lipocalin) is a secreted glycoprotein involved in several biological functions, including the transport of small lipophilic ligands across cell membranes, limitation of bacterial growth by iron sequestration, and the mesenchymal to epithelial transition. LCN2 overexpression, however, has been linked with poorer survival in patients with breast cancer, and to multiple disorders including aggressive cancer subtypes. Studies to unveil the mechanisms that drive IBC aggressiveness behavior revealed a significantly higher expression of lipocalin 2 in IBC tumors versus non-IBC breast cancer tumors, independently of the molecular subtype. In vitro studies with distinct IBC and non-IBC molecular subtypes exhibited the same tendency ().
The discovered implications of LC2 in IBC aggressiveness led to the strategic identification of small molecules that specifically inhibit the glycoprotein, demonstrating high selectivity towards LCN2 in vitro. ZINC00784494, ZINC00640089, ZINC00230567, and ZINC00829534 were identified from a library of 25,000 compounds. These small molecules selectively target the LCN2-calyx, the region with key functional groups for siderophores recognition. The LCN2 inhibitors significantly decreased cell proliferation, viability, colony formation and AKT phosphorylation in IBC cells. These LCN2 small inhibitor molecules demonstrate potential for the treatment of inflammatory breast cancer, other aggressive cancer subtypes, and a variety of LCN2-associated disorders.
Further details:

Santiago-Sánchez, G. S., Noriega-Rivera, R., Hernández-O’Farrill, E., Valiyeva, F., Quiñones-Diaz, B., Villodre, E. S., Debeb, B. G., et al. (2021). Targeting Lipocalin-2 in Inflammatory Breast Cancer Cells with Small Interference RNA and Small Molecule Inhibitors. International Journal of Molecular Sciences, 22(16), 8581. MDPI AG. PMCID: PMC8395282
Santiago-Sánchez, G. S., Pita-Grisanti, V., Quiñones-Díaz, B., Gumpper, K., Cruz-Monserrate, Z., & Vivas-Mejía, P. E. (2020). Biological Functions and Therapeutic Potential of Lipocalin 2 in Cancer. International journal of molecular sciences, 21(12), 4365. PMCID: PMC7352275
Villodre, E. S., Hu, X., Larson, R., Finetti, P., Gomez, K., Balema, W., Stecklein, S. R., Santiago-Sanchez, G., Krishnamurthy, S., Song, J., Su, X., Ueno, N. T., Tripathy, D., Van Laere, S., Bertucci, F., Vivas-Mejía, P., Woodward, W. A., & Debeb, B. G. (2021). Lipocalin 2 promotes inflammatory breast cancer tumorigenesis and skin invasion. Molecular oncology, 10.1002/1878-0261.13074. Advance online publication. PMID: 34342930

Stage of Development
The Technology Readiness Level (TRL) is estimated at 3.

LCN2 (NGAL) direct and selective post-translational inhibition
Can be readily synthesized
Potential use in combination therapies
Lead compounds for the developments of novel drugs against LCN2
Can help determine the role of LCN2 in different diseases


Inflammatory breast cancer
Other aggressive cancers, including metastatic breast cancer
LCN2 (NGAL) associated disorders:
acute renal injury
age-related macular degeneration
psoriasis and psoriatic arthritis
inflammatory diseases
metabolic dysregulation
type 2 diabetes
cardiac hypertrophy
heart failure


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