Structural Biochemistry/Tyrosine Kinase Inhibitors
Tyrosine Kinase Inhibitors are drugs that can be used to disrupt the Tyrosine phosphorylation process necessary in cell signaling near the surface of the cell.
Scientists have discovered that many diseases, cancer being a major one, use this pathway as a crucial step in the development of the diseases. Cancers use this process as if there is a mutation that leads to the production of many receptors or the production of a receptor and its growth factor, the signal becomes greater and more consistent. Thus, if scientists are able to disrupt this signal transduction process, there is reason to believe that the development of cancer can be temporarily halted or altogether stopped. This concept has led scientists to term these advances as "Signal transduction therapy".
Protein Tyrosine Kinases (PTK) are proteins that specialize in the signaling between cells and within cells. Under this category are also proteins such as Receptor Protein Tyrosine Kinases (RPTK). These are proteins that span the cell membrane, having a domain facing outward (in the cells surroundings), and having a domain inside the cell. This setup makes it optimal for this type of the protein to transmit messages from outside the cell to inside the cell or vice versa.
Some Examples of Drugs that are in the Process of Being Discovered that Would Help in Signal Transduction Therapy
1. Tyrphostins - these molecules are competitive with the substrate and noncompetitive with ATP. At first, scientists discovered some natural occurring compounds that worked, but were not very selective or potent. However, with some minor chemical adjustments, the first class of tyrphostins were created. The first class of tyrphostins demonstrated that it is possible to hinder the activity of a specific PTK without being toxic to the cells or disrupting normal cellular processes.
2. STI-571 - This drug was first discovered as means to hinder the activity of the enzyme PTK Bcr-Abl kinase, which was an enzyme critical in the stages of development for chronic myelogenous leukemia (CML). STI-571 works by interaction between the inhibitor and the amino acids that are part of the ATP-binding area of the PTK. This drug has been carried all the way to clinical trials and has shown effect in Leukemia patients in the chronic phase. However, patients with advanced forms of the disease faced relapse. STI-571 is also used to treat other diseases such as gastrointestinal stromal tumor.
3. BMS-354825 - This drug is used to treat patients that have become resistant to the treatment of STI-571. This inhibitor works on both the Bcr-Abl kinase protein and the Src kinase protein and less specific than STI-571. The difference between this drug and STI-571 is that it binds to the active state of the protein while STI-571 works by binding to the inactive state of the protein.
4. Gefitinib - This drug binds at the ATP site and is used for the treatment of non-small cell lung cancer (NSCLC). This drug has been in the clinic since 2002 but has discovered to be only effective for a very small percentage of patients. This small percentage of patients have activating mutations in the kinase domain. Gefitinib was supposed to be a EGFR kinase domain inhibitor. However, discoveries revealed that the survival of the tumor did not depend entirely on the use of EGFR kinase. Thus, it was for awhile difficult to tell whether Gefitinib was ineffective because of the inhibition of EGFR or the inability of the drug to occupy the receptor for a long period of time. Recent studies show that inhibitors of the EGFR kinase will only be useful if the receptor plays a major role in the survival of the cancer or if the drug can be combined with other signal tranduction agents to cause certain cancer cells to kill themselves.
5. AG 490 - This drug was used to inhibit a protein called Jak-2, which was a protein that played a crucial role in cytokine signaling. Amplified behavior of the Jak-2 protein was discovered to be linked to many leukemias, lymphomas, and some metastatic cancers. Ag 490 inhibited the Jak-2 pathway, thus inhibiting the expression of the oncogenic phenotype. Because this drug does not inhibit the Jak-2 protein through the disruption of signaling or cell growth, it was also experimented in unison with immunotherapy. Even though immunotherapy does not directly link to the elimination of already existent tumors, it does aid greatly with the continuation of a tumor free existence once the patient has rid themselves of a substantial volume of their tumor. AG 490, used in conjunction with interleukin (IL)-12 was proven to be effective in inducing antitumor responses in the immune system.
An Interesting Comparison Between STI-571 and PD173955
Both inhibitors work by binding to the ATP site of the kinase domain. However, they bind differently due to structural considerations; STI-571 binds to more amino acids than PD173955 does. Therefore, STI-571 only binds to a specific inactive structure of the kinase while PD173955 binds is less specific. One reason why PD173955 has proven to be more effective than STI-571 has been revealed through the fact that PD173955 can bind to multiple conformations of the kinase protein and is less specific to the state of the activation loop. STI-571 on the other hand, requires a specific inactive structure of the kinase in order to bind and thus does not bind as easily. This has led scientists to conclude that even though there are certain ATP-competitive inhibitors with a similar basic structure, the difference in functional groups really defines what that specific molecule or drug will bind to.
Levitzki, Alexander, and Eyal Mishani. Tyrphostins and Other Tyrosine Kinase Inhibitors. Rep. Annual Review of Biochemistry. Web. 29 Oct. 2011. <http://www.annualreviews.org/doi/abs/10.1146/annurev.biochem.75.103004.142657?url_ver=Z39.88-2003&rfr_dat=cr_pub%3Dpubmed&rfr_id=ori%3Arid%3Acrossref.org&journalCode=biochem>.