A non-redox reactive, tumor cell-selective inhibitor of mitogen-activated protein kinase phosphatases sensitizes breast cancer cells to lymphokine-activated killer (LAK) cell activity

Selectively killing cancer cells without harming healthy tissue remains a chief challenge in oncology. Although the scientific literature suggests that targeting dual-specificity mitogen-activated protein kinase phosphatases (DUSP-MKPs) may provide this much-sought specificity, looming toxicity concerns have stymied progress. To combat these fears, researchers at the University of Pittsburgh identified a small molecule DUSP-MKP-inhibitor called BCI-215 that selectively affects the survival of tumor cells without conferring general toxicity to the surrounding tissue. It does so in part through a novel mechanism that turns the patient’s own immune system against the invading cancer.

Technology Description

Mechanistically, BCI-215 targets cell signaling pathways specific to cancer. In human breast cancer cells, BCI-215 hampered survival by inhibiting cell movement, causing programmed cell death and sensitizing cells to immune system killer cells. Healthy human liver cells suffered none of these ill effects from the drug when tested in cell culture.

Advantages

Selectively kills cancer cells without the risk of increased toxicity
Non-necrotizing properties avoid the complications associated with tumor lysis syndrome and resultant inactivation of immune cells

Applications

Treating breast cancer
Hypothetical applications in treating other cancers
Boosting immune responses in aging or otherwise immune-suppressed patients

Stage of Development

In vitro data

IP Status

US 9,127,016 B2
US 9,439,877 B2

Innovators

Andreas Vogt, PhD

Associate Professor, Computational and Systems Biology
Group Leader, Small Organism Discovery and Projects, Drug Discovery Institute

Dr. Vogt’s primary research interest is the discovery of new therapeutic agents for diseases related to cell proliferation and intra- and extracellular signaling. Specific targets of interest are mitogen-activated protein kinase phosphatases (MKPs) and histone deacetylases – cellular enzymes involved in cancer, regeneration, and immunity that have largely eluded discovery efforts. An important part of his research is the development of analysis tools to increase information content of biological assays and to enable small molecule drug discovery in multidimensional cell systems and whole multicellular organisms such as zebrafish.

Education

PhD, Pharmaceutical Chemistry, University of Hamburg, Germany
BS, Pharmacy, University of Hamburg, Germany

Representative Publications

Ngo M, Wechter N, Tsai E, Shun T, Gough A, Schurdak M, Schwacha A, Vogt A. A High Throughput Assay for Inhibitors of Defective DNA Replication Based upon Multivariate Analysis of Yeast Growth Kinetics. SLAS Discovery. 2019, 1: 1-13

Saydmohammed M, Vollmer LL, Onuoha EO, Maskrey TS, Gibson G, Watkins SC, Wipf P, Vogt A, Tsang M. A High-Content Screen Reveals New Small-Molecule Enhancers of Ras/Mapk Signaling as Probes for Zebrafish Heart Development. Molecules. 2018, 23: 7

Hukriede N, Vogt A, de Cae. Drug Discovery to Halt the Progression of Acute Kidney Injury to Chronic Kidney Disease: A Case for Phenotypic Drug Discovery in Acute Kidney Injury. Nephron, 2017.

Michael Tsang, PhD

Professor, University of Pittsburgh School of Medicine, Department of Developmental Biology

Dr. Tsang’s lab focuses on the role of fibroblast growth factor (FGF) signaling in zebrafish organogenesis. His team has established transgenic zebrafish that reports on FGF signaling in live embryos. These fish act as biosensors for FGF activity and allow the possibility to rapidly screen chemical libraries for novel compounds that modulate the FGF pathway. These small molecules can potentially be developed into novel therapeutics in the treatment of FGF-related disorders.

Education

Postdoctoral, NICHD/NIH
PhD, Molecular Biology, University College Dublin, Ireland
BS, Pharmacology, University College Dublin, Ireland

Representative Publications

Saydmohammed M, Yagi H, Calderon M, Clark MJ, Feinstein T, Sun M, Stolz DB, Watkins SC, Amack JD, Lo CW, Tsang M. Vertebrate myosin 1d regulates left-right organizer morphogenesis and laterality. Nat Commun. 2018 Aug 23;9(1):3381.

Missinato MA, Saydmohammed M, Zuppo DA, Rao KS, Opie GW, Kühn B, Tsang M. Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration. Development. 2018 Mar 6;145(5).

Liu J, Hemphill J, Samanta S, Tsang M, Deiters A. Genetic Code Expansion in Zebrafish Embryos and Its Application to Optical Control of Cell Signaling. J Am Chem Soc. 2017 Jul 12;139(27):9100-9103