Novel compounds and screening technologies to develop a new class of cancertherapeutics that target the Ras oncogene
Mark R. Philips, MD
Professor, Departments of Medicine, Cell Biology and Pharmacology
Background and Description of Technology:
Ras is the most important target in human cancer as it is mutated in over 30% of all human malignancy, playing a central role in oncogenesis and tumor maintenance in 90% of pancreatic cancers, 50% of colon cancers and 50% of the most aggressive lung cancers. Since the 1990s, a large but unsuccessful effort by the pharmaceutical industry has focused on developing cancer drugs that inhibit Ras trafficking, known as farnesyl transferase inhibitors (FTIs). Therefore, there is significant need for a new class of agents that effectively interfere with Ras function. The lack of FTI efficacy can be explained given that three enzymes are involved in the posttranslational modifications of Ras: FTase (target of FTIs), Rce1 and Icmt. Of those, only Icmt is in a class by itself and there is no alternative enzyme to take over when it is inhibited or absent. Therefore, Icmtis a very attractive target to develop Ras inhibitors that can act either as stand-alone cancer therapeutics or in synergistic combinations with existing FTIs. Furthermore, novel high-throughput screening technologies are sorely needed to identify new lead compounds active in the Ras trafficking pathway.
Icmt was cloned and characterized by Dr. Philips. His work includes two unique technologies at different stages of development, both focused on the Ras trafficking pathway. The first are derivatives of lead compounds already identified as Icmt inhibitors by other groups. The derivatives are far superior to those previously disclosed, with medicinal chemistry that provides for favorable drug properties and IP protection.
The second technology is a novel, quantitative screen for compounds that cause the discharge of K-Ras from cellular membranes. K-Ras is the Ras isoform most important in human cancer and its discharge from cellular membranes is a long sought mechanism for neutralizing oncogenic K-Ras. Dr. Philipʼs screening system is unique and highly innovative and has a high potential of identifying new lead compounds in an unbiased fashion. It provides a much more quantitative and less ambiguous assay compared to existing methods and is far better suited to drug development.
Patents have been issued and applications filed covering Icmt as a potential target and on polypeptides and antibodies directed against Icmt, as well as K-Ras screening assays and related inventions. NYU is seeking commercial partners to develop anti-Rastherapies based on these technologies.