Novel small molecule inhibitors of c-Met signaling; these small molecules selectively bind to c-Met and have an IC50 in the micromolar range.

Aberrant c Met signaling is documented in a wide variety of malignancies and occurs via several mechanisms including amplification of c-Met (increased gene copy number), point mutations in the gene encoding c-Met, receptor over expression, and ligand dependent autocrine/paracrine receptor activation. This application describes novel small molecule inhibitors of c-Met signaling.  The small molecules selectively bind to c-Met and have an IC50 in the micromolar range. The small molecules belong to two different families.  One family of small molecules reduces the level of c Met expression via receptor down-regulation and blocks ATP binding.  The other family of small molecules block ATP binding without inducing receptor down-regulation.  Evidence suggests that the second family of compounds bind to both active and inactive conformations of c-Met.

 

Applications:

Therapy for cancers associated with aberrant c-Met signaling, for example bladder, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, kidney, liver, lung, nasopharyngeal, ovarian, pancreatic, prostate and thyroid cancers, as well as cholangiocarconoma, osteosarcoma, rhabdomyosarcoma, synovial sarcoma Kaposi's sarcoma, leiomyosarcomas and MFH/fibrosarcoma.  In addition to these malignancies, aberrant c Met signaling is associated with hematological malignancies such as acute myelogenous leukemia, adult T cell leukemia, chronic myeloid leukemia, lymphomas and multiple myeloma as well as other tumors like melanoma, mesothelioma, Wilms' tumor, glioblastomata and astrocytomas.

 

Market:

Although the percentage of cancers associated with aberrant c Met signaling is not yet well established, the wide variety of cancers associated with aberrant c Met signaling are indicative of a potentially large market for these compounds.  For example, worldwide over 1 million persons per year are diagnosed with colorectal cancer and it is the most common gastrointestinal cancer in industrialized countries.  In one study of colorectal cancer 69% of the patients had at least a two-fold elevation of cMet mRNA and 48% of the patients had at least a ten fold elevation of c Met mRNA.  In a study of breast cancer, 22% of patients with invasive ductal breast tumor specimens exhibited strong expression of c Met and patients exhibiting c Met expression had only a 52% 5 year survival rate compared with an 89% 5 year survival rate in patients with normal c Met levels.

 

Publications:

The patent application has not been published. There are no journal articles available related to this work.

 

Preclinical

U.S. Provisional Application No. 61/041,523 filed 01 Apr 2008 (HHS Reference No. E-332-2007/0-US-01)

 

Inventors:

Donald P. Bottaro, Terrence Burke, Jr., et al. (NCI)

 

Licensing Status:

Available for licensing on an exclusive or non-exclusive basis.

 

Collaborative Research Opportunity:

The National Cancer Institute, Urologic Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize small molecule inhibitors of the HGF/c-Met signaling pathway.  Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.