Description:
RAS is the most common oncogene in human cancer, with ~20% mutation rate in human tumor overall and up to 90% in certain types of cancers (e.g. pancreatic cancer). Responsible for 76% of RAS-mutated cancers of the three RAS genes (HRAS, KRAS, and NRAS), KRAS remains a promising yet challenging therapeutic target despite research efforts for the past four decades with toxicity being a major hurdle in drug targeting. To overcome this problem, UTHealth researchers identified selected Fendiline derivatives as novel cancer therapeutic and diagnostic agents.
Background:
KRAS gene is a member of the rat sarcoma viral oncogene family (RAS), responsible for a wide range of human cancers including but not limited to leukemia, colorectal cancer, pancreatic cancer, lung cancer, and endometrial cancer. Direct targeting of KRAS has proven more challenging. Several potent and highly selective KRAS G12C inhibitors (e.g. AMG51023 and MRTX849) are currently advanced into human clinical trials. Nevertheless, such compounds are likely only be useful in the 15% of KRAS tumors that harbor a G12C mutation. PM localization (PML) is essential for KRAS function, and therefore, blocking oncogenic KRAS-driven signaling by preventing PM localization represents an appealing strategy, resulting in development of small molecule PDEδ inhibitors. However, toxicity concerns are raised because PDEδ has a crucial role in regulating the function of many other prenylated GTPases.
Significance and Impact:
Dr. John F. Hancock at UTHealth and his colleagues have identified novel Fendiline derivatives along with the corresponding methods for the treatment and prevention of KRAS-driven cancers. Localization of K-ras to the plasma membrane is important in order to activate downstream effector pathways. These novel Fendiline derivatives inhibited oncogenic KRAS-driven cancer cell proliferation at low dose concentrations in vitro and in vivo.
Benefits/Technology Advantages:
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Describes novel compounds, including Fendiline derivatives, inhibiting K-Ras localization onto the plasma membrane.
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Such novel compounds may be used for inhibiting the signal transduction from oncogenic K-Ras.
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Provides potential therapies for cancer, such as leukemia, colorectal cancer, pancreatic cancer, lung cancer, and endometrial cancer.
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Available pre-clinical data in K-Ras transformed pancreatic, endometrial, colorectal and lung tumor cell lines.
IP Status:
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Issued US Patent No. 12,043,602
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Issued US Patent No. 9474730
Available for licensing
Researchers:
Drs. John F. Hancock (UTHealth) and Dharini van der Hoeven
John Hancock, MA, MB, BChir, PhD, ScD
Senior Vice President of Research Strategy and Innovation, and
Executive Dean of McGovern Medical School at UTHealth Houston