A replacement for chemotherapy?
Metastasis is a process where cancer cells of primary tumors gain properties enabling them to escape from the primary tumor and move to a secondary location in the body where they develop additional tumors. This event in advanced tumor progression subsequently results in >90% of all cancer patient deaths and there are currently no effective therapies to either prevent or treat metastatic cancer. In my lab at the Washington University School of Medicine in Saint Louis, we now have developed new small molecules which potently inhibit three key proteolytic enzymes, HGFA, matriptase and hepsin, which are essential for tumor progression and metastasis.
Similar to a blocked fuel pump in a vehicle which stops a car from moving and its engine from running, these inhibitors stop cancer cell signaling by cutting off the fuel (the growth factors HGF and MSP) supply to its engines, the c-MET and RON kinase receptors. The inhibitors block the processing of both HGF and MSP by the enzymes (oil refineries) and, without the fully refined growth factors, the kinase receptors cannot turn or stay on. Depending on the cancer type, an inhibitor of one or more of these enzymes will be necessary to block signaling and metastasis. We have rationally designed a complete set of seven compound subsets encompassing all such possible combinations in hand which inhibit:
- HGFA, matriptase and hepsin
- HGFA and matriptase
- HGFA and hepsin
- matriptase and hepsin
- HGFA only
- matriptase only
- hepsin only
These exciting compounds are a powerful toolkit of new drugs for the treatment and prevention of metastatic cancer. The inhibitors, now in preclinical testing, have potential to 1) treat tumors that are chemoresistant to targeted kinase inhibitors and 2) to replace standard adjunct chemotherapy (post-surgery) altogether with safer and more effective therapeutics without the debilitating side-effects normally encountered in current cancer therapy.
James W. Janetka, Ph.D.
Associate Professor of Biochemistry & Molecular Biophysics
Adjunct Professor of Chemistry, Washington University
Saint Louis, USA
Structure-based discovery of small molecule hepsin and HGFA protease inhibitors: Evaluation of potency and selectivity derived from distinct binding pockets.
Franco FM, Jones DE, Harris PK, Han Z, Wildman SA, Jarvis CM, Janetka JW.
Bioorg Med Chem. 2015 May 15
|Deep Molecular Profiling to understand the biology… Alzheimer disease (AD) is a complex, polygenic disease with genetic, cellular, pathologic, and clinical heterogeneity. Advances in high-throughput sequencing and omics technologies have accelerated the drive toward personalized medicine. Human…|
|A new strategy for immune manipulation of advanced… The biological cancer hallmarks and the current model In the updated ongoing model, genomic instability and inflammation are the basis of all the cancer hallmarks: sustaining proliferative signaling, evading growth…|
|Arming macrophages to stop cancer progression Macrophages are a type of immune cells that fight infection and support tissue remodeling. They are best known as phagocytes which engulf bacteria and damaged cells stimulating other immune cells.…|
|Social-economic factors predict state differences in… Media accounts of the opioid overdose epidemic emphasize the role of prescription drugs and, to a lesser extent, declining economic and social conditions. In support of the journalists’ accounts, opioid…|
|FLYWCH1 is a novel transcriptional repressor for the… There is no doubt that cancer is a devastating disease. However, restraining the cancerous cells from spreading throughout the body (invasion) will make it easier to control and possibly cure…|
|Exercise inhibits cancer: the mechanosensitive state… Surprisingly, researchers find that tumor cells are sensitive to mechanical stresses. This may provide new ways to treat cancers without the severe side-effects of many therapies. Because mechanosensitivity of cancer…|