Small molecule inhibitors as emerging cancer therapeutics

Cancer is one of the major health problems. Although traditional therapies have been effective in cancer treatment, they often have adverse side effects due to their nonspecific action on both normal and tumor cells. Therefore, targeted treatment strategies using small molecule inhibitors are being extensively studied. These compounds are usually ≤500Da size and are often administered orally. In principle, small molecule compounds can be developed to target any portion of a molecule, regardless of the target’s cellular location. In this blog entry, we provide a summary of the small molecule inhibitors (SMIs) used in the cancer therapy.

• 1) Introduction
• 2) Small Molecule Inhibitors
• 3) List of small molecule inhibitors for cancer therapy
• 4) Limitations of the Small Molecules
• 5) Conclusions
• 6) References

1) Introduction

The traditional means of cancer management are chemotherapy, radiation therapy and surgery. Chemotherapy that involves the use of a single drug at a time (single-agent chemotherapy) or several drugs (combination therapy) usually target killing of rapidly dividing cancer cells. To overcome the drawbacks of traditional cancer therapies, the approach has been to search for specific molecular targets for selective elimination of cancer cells. Such targeted therapy would conceptually be more specific than the traditional non-targeted therapy. The two main approaches of specific molecular targeting available for use in clinical practice are small molecule agents and monoclonal antibodies (mAbs) [1]. When compared to mAbs which are usually large molecular weight proteins of around 150kDa, small molecule cancer drugs are much smaller in size (≤500Da) and thus can translocate through plasma membranes. On the contrary, the mAbs can only act on molecules that are expressed on the cell surface [8]. The small molecule inhibitors are also comparatively cost effective and are amenable to oral administration while the mAbs are mostly administered intravenously [2].

2) Small Molecule Inhibitors

Small molecule cancer drugs, because of their small size, have been successfully used to target the extracellular, cell surface ligand-binding receptors as well as the intracellular proteins, including anti-apoptotic proteins that play a key role in transducing downstream signalling for cell growth and metastasis promotion. Most of these drugs inhibit critical cancer targets such as serine/threonine/tyrosine kinases, matrix metalloproteinases (MMPs), heat shock proteins (HSPs), proteosome and other proteins playing a role in signal transduction pathways.

3) List of Small Molecule Inhibitors for cancer therapy

Many cancer therapeutic drugs have been approved for use and several more are being studied in clinical trials.

4) Limitation of the use of Small Molecules

More than 20 small molecule drugs have been approved for clinical use and are being successfully used in cancer treatment. Still, there are certain limitations that are to be considered and overcome while designing more active drugs so as to reduce the failure rates of the drugs at the clinical level. Certain small molecule inhibitors bind to multiple molecular targets including cell surface receptors and other intracellular proteins thus increasing the risk of toxicity [3]. Most of the small molecule drugs have a short life span, thus requiring daily dosing which is not the case with therapeutic mAbs that have a longer life span [3].

5) Conclusions

Over the last few decades, the success of small molecule cancer drugs over conventional chemotherapy has been clearly demonstrated. Majority of the inhibitors that have been developed and currently in clinical use target the kinases, which include the receptor molecules as well as downstream regulators [4]. Labclinics includes in its catalog, the catalog from ApexBio, a leading provider of peptides, small molecules and laboratory reagents for biomedical research. Its main product line is apoptosis and epigenetics. ApexBio also provides peptide synthesis.

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6) References

[1] Wu HC, Chang DK, Huang CT (2006) Targeted Therapy for Cancer. Journal of Cancer Molecules 2: 57-66

[2] Imai K, Takaoka A (2006) Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 6: 714-727.

[3] Curigliano G, Criscitiello C. (2014) Successes and limitations of targeted cancer therapy in breast cancer. Prog Tumor Res 41: 15-35.

[4] Bari SB, Adhikari S, Surana SJ (2012) Tyrosine Kinase Receptor Inhibitors: A New Target for Anticancer Drug Development. Journal of Pharma Sci Tech 1: 36-45.