What is Kinases?

Kinases are enzymes that transfer a phosphate group from an ATP molecule to a protein substrate. This protein modification, known as phosphorylation, can have a broad range of biological effects depending on the protein that is modified.

Overview

Kinases chemically modify other proteins or themselves by transferring a phosphate group from ATP to an amino acid residue of another protein, a process known as phosphorylation. Phosphorylation of a substrate protein can result in a variety of biological effects including activation or inactivation of enzymes, cell signaling, and regulation of the cell cycle.

As the biological effects of phosphorylation vary widely depending on the protein modified, kinases are generally classified by the type of amino acid residue that is modified on the substrate protein, generally serine, threonine, or tyrosine.1

Kinase class Examples in humans
Serine-Threonine Kinase Casein Kinase 1 (CK1)
Protein Kinase C (PKC)
Cyclin Dependent Kinase (CDK)
Glycogen Synthase Kinase 3 (GSK3)
Tyrosine Kinases Receptor-Linked Kinases such as Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR)
Non-Receptor Src Kinases
Raf Kinases

Existing Products

Most kinase inhibitors in development are drugs that target the ATP binding site on the kinase rather than the protein substrate binding site. Substrate binding sites of enzymes are often targeted for small molecule drug development. However, in kinases these regions are shallow and difficult to target with small molecule inhibitors. As the ATP binding site is reasonably conserved across families of protein kinases, it is challenging to engineer inhibitor selectivity between related kinases. Even though this binding site is conserved across families of protein kinases, it is still possible to design inhibitors that are reasonably selective.2

Protein kinases represent 20-30% of all drug discovery programs [3] and kinase inhibitors are being actively pursued especially in oncology indications. There is also recent interest in targeting kinases to treat inflammatory disorders and central nervous system (CNS) diseases.1,4

Large Pharma Companies that are pursuing kinase targets include AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, and Pfizer. Smaller Biopharma companies such as Array BioPharma and Exelixis are also active in this space.1

There are several kinase inhibitors currently on the market. Examples of FDA approved drugs are included in the table below.

Kinase target Disease (FDA-approved drug indication) Generic (Brand) Manufacturer
Bcr-Abl, PDGFR, c-kit Chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GIST) and certain other cancers Imatinib (Gleevec) Novartis
EGFR Certain breast, lung and other cancers Gefitinib (Iressa) AstraZeneca
EGFR Non-small cell lung cancer, pancreatic cancer and certain other cancers Elotinib (Tarceva) Roche
mTOR Immunosuppressant drug Sirolimus (Rapamune) Wyeth (now Pfizer)
Multi-kinase Advanced renal cell carcinoma and hepatocellular carcinoma Sorafenib (Nexavar) Bayer

Kinase Inhibitors as Non-Neglected Tropical Disease Therapeutics

Novartis’ Gleevec, a tyrosine kinase inhibitor was the first approved kinase inhibitor and the most commercially successful. It was initially approved by the FDA in 2001. It has been used in the US for the treatment of ten cancers including as the first-line treatment for chronic myelogenous leukemia.5

In 2011 Plexxikon’s Zelboraf, a small molecule B-raf kinase inhibitor was approved for the treatment of metastatic melanoma in patients who carry the V600E mutation in the B-raf gene.6

Most kinase inhibitors are being developed for cancer indications. Inflammatory indications account for nearly half the kinase inhibitors being developed for diseases other than cancer. p38 kinase has been targeted for treatment of inflammatory disorders such as rheumatoid arthritis.1 Kinase inhibitors are also being developed for treatment of central nervous system (CNS) diseases. Noscira has drug candidate currently in Phase II trials for supranuclear palsy. Other kinase inhibitors targeting neurodegenerative pathways are in the research and discovery phase.4

Kinase Inhibitors as Neglected Tropical Disease Therapeutics

There are currently no kinase inhibitors approved for the treatment of neglected tropical diseases. However, it may be possible to exploit differences in ATP binding between human and neglected tropical disease kinases to develop selective kinase inhibitors for neglected tropical disease indications. Kinases are present in parasites, including those that cause malaria, HAT and leishmaniasis, as well as in Mycobacterium tuberculosis. Some of these kinases have been validated as therapeutic targets.

References

  1. Norman, P. (2011) “Kinase Therapeutics: Pipeline Assessment and Commercial Prospects.” INSIGHT Pharma Report
  2. Zhang, J. et al. (2009) “Targeting cancer with small molecule kinase inhibitors.” Nature Reviews, Cancer. 9: 28-39
  3. Kondapalli, L. et al. (2005) “The promise of molecular targeted therapies: protein kinase inhibitors in the treatment of cutaneous malignancies.” Journal of the American Academy of Dermatology, 53(2): 291-302
  4. Dimond, P.F. (2011) “Protein Kinase Inhibitors for CNS Diseases at the Research and Discovery Phase.” Genetic Engineering and Biotechnology News (GEN) June 1
  5. National Cancer Institute, Gleevec: Questions and Answers
  6. Plexxikon Press release, available here.

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.

Pipline

Analysis

In the area of neglected tropical diseases, kinase inhibitor development is in the early discovery and target validation stage. There are no kinase inhibitors in clinical trials for these indications currently.

A large number of kinase inhibitor libraries with drug-like properties are available for various kinase targets, as kinases have been investigated by the pharma and biotech sectors for cancer and other indications. These libraries can be screened for selectivity to the neglected disease target. Therefore, an opportunity for repurposing without minimal additional development exists. For example, glycogen synthase kinase 3 (GSK3) inhibitors have been explored in drug development for Alzheimer’s disease. Trypanosoma brucei the causative agent of HAT expresses two kinases with homology to GSK3 that can be targeted with this class of inhibitors.5

There are also risks involved with this strategy. If the neglected disease target kinase and the human kinase are too similar, the inhibitor may have undesirable effects. Also, if there are multiple kinases that can compensate, then inhibiting one kinase alone may not be sufficient to kill the parasite or bacteria. 

Examples of validated neglected disease kinase targets are listed in the table below.

Validated kinase target Disease
PKnG (Protein Kinase G) Tuberculosis1
PKnB (Protein Kinase B) Tuberculosis1
CK1 (casein kinase 1) Leishmaniasis2
Aurora kinase-1 HAT3
P13 / mTOR kinase HAT4
GSK-3 (glycogen synthase kinase-3) HAT5

MMV is also supporting a program at Monash University for screening for inhibitors for Plasmodium falciparum kinases in a multiplexed affinity based assay. The kinome-wide screen will enable the identification of compounds that inhibit P.falciparum kinases, a majority of which are also present in P.vivax.6

References

  1. Vichem Chemie Tuberculosis Drug Discovery
  2. Alloco J.J. et al. (2006) "Inhibitors of casein kinase 1 block the growth of Leishmania major promastigotes in vitro". International Journal for Parasitology 36: 1249-1259
  3. Jetton N. et al. (2009) "The cell cycle as a therapeutic target against Trypanosoma brucei: Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms". Molecular Microbiology 72(2): 442-458
  4. Diaz-Gonzalez R. et al. (2011) "The susceptibility of trypanosomatid pathogens to P13/mTOR kinase inhibitors affords a new opportunity for drug repurposing". PLoS Neglected Tropical Diseases 5(8): e1297
  5. Odour R.O. et al. (2011) "Trypanosoma brucei glycogen synthase kinase-3, a target for anti-trypanosomal drug development: A public-private partnership to identify novel leads". PLoS Neglected Tropical Diseases 5(4): e1017
  6. Medicines for Malaria Venture (MMV) Protein Kinases of P.falciparum lead generation

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.

Database Resources

  • KinBase, the kinase database at Sugen/Salk includes kinases from worms and Leishmania major.
  • Kinase Sequence Database at UCSF contains protein kinase sequences grouped into families based on homology of the catalytic domain. The database currently features a total of 287 families, which contain 7128 protein kinases from 948 organisms.
  • GVK Bio has compiled a kinase inhibitor database that is available for licensing on a non-exclusive basis. This database is compiled from chemical, biological, and pharmacological information of kinase inhibitors from journal publications and US and international patents.
  • University of Dundee has a kinase panel of over a 100 human kinases belonging to various classes. This panel can be used to counterscreen against the human kinases in NTD kinase inhibitor development.
  • University of Dundee also offers kinase profiling services where the assay used is the 33P-ATP filter binding assay. This can be used to confirm results obtained from fluorescent assays.
  • Vichem Chemie has a nested chemical library containing most of best published kinase inhibitors and several proprietary structures against 124 kinases. It offers a contract service model to find inhibitors to specific kinase targets. 

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.