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IODVA1, a Guanidinobenzimidazole Derivative with in vivo Activity Against Ras-Driven Cancer Models

62 Pages Posted: 24 May 2019 Sneak Peek Status: Review Complete

See all articles by Anjelika Gasilina

Anjelika Gasilina

Children’s Hospital Research Foundation - Division of Experimental Hematology and Cancer Biology

Gurdat Premnauth

University of Cincinnati

Purujit Gurjar

University of Cincinnati

Jacek Biesiada

Cincinnati Children's Hospital Medical Center - Division of Biomedical Informatics

Shailaja Hegde

Children’s Hospital Research Foundation - Division of Experimental Hematology and Cancer Biology

David Milewski

Cincinnati Children’s Hospital Research Foundation

Gang Ma

Children’s Hospital Research Foundation - Division of Experimental Hematology and Cancer Biology

Tanya V. Kalin

Cincinnati Children’s Hospital Research Foundation

Edward Merino

University of Cincinnati

Jarek Meller

Cincinnati Children's Hospital Medical Center - Division of Biomedical Informatics

William Seibel

Cincinnati Children's Hospital Medical Center

José A. cancelas

Children’s Hospital Research Foundation - Division of Experimental Hematology and Cancer Biology

Lisa Privette Vinnedge

Cincinnati Children's Hospital Medical Center

Nicolas N. Nassar

Children’s Hospital Research Foundation - Division of Experimental Hematology and Cancer Biology

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Abstract

We report the synthesis and preliminary characterization of IODVA1, a potent small molecule that is active in xenograft mouse models of Ras-driven lung and breast cancers. In an effort to inhibit oncogenic Ras signaling, we combined in silico screening with inhibition of proliferation and colony formation of Ras-driven cells. NSC124205 fulfilled all criteria. HPLC analysis revealed that NSC124205 was a mixture of at least three compounds, from which IODVA1 was determined to be the active component. IODVA1 decreased 2D proliferation, 3D spheroid formation, spreading and lamellipodia formation in breast cancer cells. IODVA1 significantly impaired xenograft tumor growth of Ras-driven cancer cells with no observable toxicity. Immuno-histochemistry analysis of tumor sections suggests that cell death occurs by increased apoptosis. Our data suggest that IODVA1 targets a node used by Ras to regulate cell survival, spreading, and movement including lamellipodia formation. Therefore, IODVA1 holds promise as an anti-tumor therapeutic agent.

Keywords: Drug Screening, drug discovery, Small Molecule Inhibitor, Medicinal chemistry, Rat-Driven Cancer, Breast Cancer, lung cancer, Lamellipodia, Actin.

Suggested Citation

Gasilina, Anjelika and Premnauth, Gurdat and Gurjar, Purujit and Biesiada, Jacek and Hegde, Shailaja and Milewski, David and Ma, Gang and Kalin, Tanya V. and Merino, Edward and Meller, Jarek and Seibel, William and cancelas, José A. and Privette Vinnedge, Lisa and Nassar, Nicolas N., IODVA1, a Guanidinobenzimidazole Derivative with in vivo Activity Against Ras-Driven Cancer Models (May 24, 2019). CELL-CHEMICAL-BIOLOGY-D-19-00172. Available at SSRN: https://ssrn.com/abstract=3393521 or http://dx.doi.org/10.2139/ssrn.3393521
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Anjelika Gasilina

Children’s Hospital Research Foundation - Division of Experimental Hematology and Cancer Biology

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Gurdat Premnauth

University of Cincinnati

Cincinnati, OH 45221-0389
United States

Purujit Gurjar

University of Cincinnati

Cincinnati, OH 45221-0389
United States

Jacek Biesiada

Cincinnati Children's Hospital Medical Center - Division of Biomedical Informatics ( email )

Cincinnati, OH 45229
United States

Shailaja Hegde

Children’s Hospital Research Foundation - Division of Experimental Hematology and Cancer Biology

3333 Burnet Avenue
Cincinnati, OH 45229
United States

David Milewski

Cincinnati Children’s Hospital Research Foundation

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Gang Ma

Children’s Hospital Research Foundation - Division of Experimental Hematology and Cancer Biology

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Tanya V. Kalin

Cincinnati Children’s Hospital Research Foundation

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Edward Merino

University of Cincinnati

Cincinnati, OH 45221-0389
United States

Jarek Meller

Cincinnati Children's Hospital Medical Center - Division of Biomedical Informatics ( email )

Cincinnati, OH 45229
United States

William Seibel

Cincinnati Children's Hospital Medical Center ( email )

3333 Burnet Avenue
Cincinnati, OH 45229
United States

José A. Cancelas

Children’s Hospital Research Foundation - Division of Experimental Hematology and Cancer Biology ( email )

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Lisa Privette Vinnedge

Cincinnati Children's Hospital Medical Center

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Nicolas N. Nassar (Contact Author)

Children’s Hospital Research Foundation - Division of Experimental Hematology and Cancer Biology ( email )

3333 Burnet Avenue
Cincinnati, OH 45229
United States

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