New inhibitors of a cancer-causing protein may lead to targeted therapeutics

The activity of protein kinases, a large class of signaling molecules, must be closely regulated or signaling chaos arises within cells. Signaling chaos sets off a process that is implicated in the development of cancers, including solid tumors. Because protein kinases have a central role in cell signaling, researchers have devoted decades of investigation to developing protein kinase inhibitors.

One kinase inhibitor, a drug called Imatinib (or Gleevec), illustrates the profound potential of kinase inhibitors in cancer treatment. The hyperactivity of the Abl kinase is the most common cause of chronic myelogenic leukemia (CML). Imatinab is routinely used to treat CML. Since Imatinib’s Food and Drug Administration-approval in 2001, deaths related to CML have dropped significantly.

Src kinase inhibitors have been used in clinical trials as experimental treatments for many types of solid tumors. However, in contrast to the success of Imatinib for treating CML, a drug based on inhibiting the Src kinase has not been effective in treating solid tumors.

“Think of kinases as a traffic light system that is regulated to keep traffic flowing properly,” says Dr. Seeliger. “But if all lights on a road system are green, chaos occurs. The Src kinase is a dangerous ‘traffic light’ when it stays green. The challenge is to inhibit Src kinase, in other words make it a ‘red light,’ without stopping other Src family of kinases from staying ‘green’ to keep the traffic moving safely.”

In “Highly specific, bisubstrate-competitive Src inhibitors from DNA-templated macrocycles,” the researchers successfully completed two steps that are necessary for the development of new Src kinase-targeted drugs.

First, under the direction of David Liu, Ph.D., Professor, Department of Chemistry, Harvard University, the team developed chemical inhibitors of Src kinase. Dr. Seeliger’s laboratory at Stony Brook then determined the three-dimensional structure of these inhibitors bound to the Src kinase. This second step enabled the team to explain why the inhibitors work to stop the Src kinase but not the other kinases in cultured mammalian cells.

“Using this method, the precise molecular basis of the inhibitory mechanism and Src kinase are revealed,” says Dr. Seeliger. “These results provide new insights into the development of Src-specific inhibitors with potential therapeutic relevance.”

Provided by Stony Brook University (news : web)

Entry prohibited for AIDS viruses: Peptide triazole inhibitors disrupt cell-free HIV-1

The initial entry of HIV-1 into host cells remains a compelling yet elusive target for the development of agents to prevent infection, a critical need in the fight against the global AIDS epidemic.

A collaborative research effort led by Irwin Chaiken at Drexel University and Drexel University College of Medicine (Philadelphia, PA, USA) has demonstrated that modified peptide triazole inhibitors which specifically target the HIV-1 envelope (Env) protein gp120 can physically disrupt virus particles in the absence of host cells, and the results are reported in ChemMedChem.

The Drexel team found that under conditions similar to those at which a newly designed peptide triazole (KR13) inhibits infection of host cells by an HIV-1 pseudovirus, it also causes virus rupture and release of an internal HIV-1 protein called gag p24 when incubated with virus alone.

Both inhibition of cell infection and p24 release are enhanced substantially by the multivalent display of KR13 on gold nanoparticles.

The novel antagonist design and reported characterization data could lead to the creation of a virucide to suppress initial HIV-1 infection, viremia in infected individuals, and the spread of infection between individuals. Such agents could be used for HIV-1 microbicides and therapeutics.

These results also suggest that ligand-specific pathogen rupture may be possible for other viruses that contain metastable prefusion surface protein complexes, such as influenza, Ebola, and Dengue.

More information: Irwin Chaiken, Cell-Free HIV-1 Virucidal Action by Modified Peptide Triazole Inhibitors of Env gp120, ChemMedChem 2011, 6, No. 8, http://dx.doi.org/ … dc.201100177

Combining two peptide inhibitors might block tumor growth

A new study suggests that combining two experimental anticancer peptide agents might simultaneously block formation of new tumor blood vessels while also inhibiting the growth of tumor cells.

This early test of the two agents in a breast cancer model suggests that the double hit can stifle tumor progression, avoid drug resistance and cause few side effects, say researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) who developed the agents and evaluated their effectiveness in laboratory and animal tests.

The scientists designed one of the agents to prevent human epithelial growth factor from interacting with HER-2, a molecule that marks a particularly aggressive form of breast cancer. The other inhibitor blocks the action of vascular endothelial growth factor (VEGF), which stimulates the growth of new blood vessels that tumors need to grow beyond a certain size.

The findings are described in two papers published online in the Journal of Biological Chemistry. One presents the development of a novel VEGF inhibitor; the other describes the HER-2 inhibitor and the preclinical testing of the two agents together.

"When we combined our peptide HER-2 inhibitor with the VEGF peptide that inhibits angiogenesis, we observed significant additive benefits in reducing tumor burdens in preclinical studies," says principal investigator Pravin Kaumaya, professor of obstetrics and gynecology, of molecular and cellular biochemistry, and of microbiology, and director of the division of vaccine development at the OSUCCC – James.

The strategy of targeting both HER-2 and VEGF pathways should also discourage the development of drug resistance, Kaumaya says, because it simultaneously inhibits two pathways that are essential for tumor survival. "Combined peptide inhibitors might be appropriate in several types of cancer to overcome acquired resistance and provide clinical benefit," he adds.

Peptide inhibitors consist of short chains of amino acids (the VEGF inhibitor is 22 amino acids long) that conform in shape to the active site of the target receptor. In addition, Kaumaya engineered the VEGF peptide to be resistant to protease, an enzyme, thereby increasing its efficacy. The shape of the peptide HER-2 inhibitor engineered by Kaumaya and his colleagues, for example, is highly specific for the HER-2 receptor. It physically binds to the receptor, which prevents another substance, called epithelial growth factor, from contacting the receptor and stimulating the cancer cells to grow.

Other categories of targeted drugs in clinical use are humanized monoclonal antibodies and small-molecule TKI inhibitors. Both groups are associated with severe side effects and are very expensive, Kaumaya says. "We believe peptide inhibitors offer non-toxic, less-expensive alternatives to humanized monoclonal antibodies and small-molecule inhibitors for the treatment of solid tumors, with the potential for improved efficacy and better clinical outcomes," he says.

Provided by Ohio State University Medical Center