On April 21, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported that researchers from the Icahn School of Medicine at Mount Sinai, led by Professor E. Premkumar Reddy, scientific founder of Onconova, have published a study describing the novel RAS-targeted mechanism of action for rigosertib in the journal Cell (Press release, Onconova, APR 21, 2016, View Source [SID:1234511258]). The paper, titled "A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling," can be accessed in the current online edition of Cell.
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RAS represents one of the most sought-after targets in cancer. Thus far the development of drugs to block RAS has been difficult, leading many to label RAS the undruggable oncogene.
"This discovery is the culmination of my laboratory’s work with RAS genes over the last three decades," said Dr. E. Premkumar Reddy, lead author of the paper and Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. "RAS genes have been a challenging target for molecular oncologists and drug developers. However, the allosteric mechanism by which rigosertib blocks activation of signaling proteins downstream of RAS may represent a new paradigm for attacking this oncogene."
The research published in Cell and carried out by a multidisciplinary team from Mount Sinai, The Scripps Cancer Research Institute, Albert Einstein College of Medicine, and the New York Structural Biology Center, demonstrated that rigosertib blocks RAS signaling by directly binding to various RAS effector proteins, including RAF and PI3-kinase. These mechanistic findings support the development of rigosertib in malignancies with over-activate RAS signaling, such as higher-risk myelodysplastic syndromes (HR-MDS). Onconova is actively enrolling patients in the global INSPIRE trial, a randomized Phase 3 study to assess the efficacy and safety of single-agent intravenous rigosertib in HR-MDS.
About Rigosertib
Rigosertib is a small molecule inhibitor of cellular signaling and acts as a Ras mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the Ras-binding domain (RBD) found in many Ras effector proteins, including the Raf kinases and PI3K. The initial therapeutic focus for rigosertib is myelodysplastic syndromes (MDS), a group of bone marrow disorders characterized by ineffective formation of blood cells that often converts into acute myeloid leukemia (AML). Clinical trials for rigosertib are being conducted at leading institutions in the United States, Europe, and the Asia-Pacific region. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.
About RAS
Point mutations in RAS genes (HRAS, KRAS and NRAS) are frequently observed in many of the most common and lethal tumors, including cancers of the pancreas, lung, colon, skin, bladder and bone marrow. RAS genes encode important intracellular proteins that when mutated activate pathways involved in cancer cell proliferation, survival and metastasis. Although molecular oncologists have made significant headway in understanding RAS mutations and their impact on cellular signaling, less progress has been made towards developing RAS-targeted drugs. Thus, there is an urgent need for new therapeutic modalities that address this important oncogene.