

Small Molecule Drugs - To Fight Cancer, Heart Failure, etc.

Ali Fethi Toprak

2017-01-01 00:00:00

In the pharmacology, a small molecule is described as a low molecular organic compound showing high binding affinity to targets of interest such as proteins, nucleic acids, or polysaccharides. This allows small molecules to alter their biological activity. Their small size allows easy transport in the body and a strong ability to diffuse across cell membranes, enabling them to reach their binding targets.
The functions of small molecules vary. In the body, natural small molecules can serve as cell signaling molecules. A number of neurotransmitters – which play a role in the communications between two nerve cells such as dopamine, acetylcholine, and epinephrine – could be given as examples of small molecules in the human body.
There are a number of small molecules used as drugs, too.  Researchers are searching for more small molecules that can be used to treat diseases in the future.

Small molecules as therapeutics
The identification of active compounds holds the key to the future development of therapeutic agents.  Upon synthesis of the analogs of these compounds, derivatives of the initially identified compound could be selected for increased activity. 
Initially, scientists investigated peptides or oligonucleotides, hoping they would have some therapeutic qualities. However, poor oral activities, rapid clearance from the body, and limited bioavailability meant that peptides were not good candidates.
Small molecules, however, which generally have molecular weights smaller than 600-700, presented themselves as interesting candidates for therapeutic use. Screening these small molecules and forming a catalog of them become a major goal in molecular biology, with the hopes of developing new treatments for various diseases.
Small molecule stimulation of nerve stem cells to maturation
It had been believed for decades that the adult mammalian brain could not grow new brain cells. Thus, learning and memory were thought to be due to new connections created between existing cells in the brain.  It is now well-established that new nerve cells are being constantly created in the brain. Scientists know that when a nerve cell sends a neurotransmitter to a stem cell it generates new nerve cells, but researchers are not sure which signaling pathways or genes are involved in this process.
Researchers at University of Texas Southwestern Medical Center at Dallas have discovered a small molecule called Isx-9 that stimulates nerve stem cells to maturate into nerve cells. Dr. Hsieh and her colleagues demonstrated that Isx-9 behaves like a neurotransmitter signal. Compared to other commonly used neurogenic simulators, Isx-9 was three times more efficient in the generation of nerve cells while also preventing the stem cells from transforming into non-nerve cells. When they cultured cells from the hippocampus with Isx-9, the researchers found that stem cells formed clusters along with the development of spiky appendages called neuritis. Their finding provides a new opportunity to investigate the signaling circuitry specifying the fate of neuronal cells and offers potential new approaches for neuro-regenerative drugs.  Using this approach, it might someday be possible to do a stem cell therapy using a patient’s own stem cells that could be grown in a culture and transformed into mature nerve cells by using small molecule induction. These could then be transplanted back into patients to treat various neurological disorders.
Development of neuroprotective small molecules
The degeneration of the hippocampus and loss of neurons occurs in the early phases of Alzheimer’s disease. Current approaches are often inadequate to treat symptoms associated with Alzheimer’s. As such, scientists are frantically searching for novel therapeutics.
The hippocampus plays a critical role in learning and memory. Researchers screened a library of 1,000 different molecules to identify the ones that can enhance neuron formation in the hippocampus of mice. This quest for a drug that could keep brain cells from dying led to the discovery of a compound: a study by doctors McKnight and Pieper found that a small molecule called P7C3 may protect newborn neurons from dying.
One advantage of such a small molecule as a drug is the availability of means to modify the compound to improve its actions. Further studies are needed, however, to see if P7C3 can block the death of mature nerve cells. Modifications may allow its usage in treating different types of diseases such as Huntington’s disease and amyotrophic lateral sclerosis. As a small molecule, P7C3 has the ability to penetrate the blood-brain barrier. It achieved stability in animal models and cell culture settings, and activity even at nanomolar concentrations.

Cardiogenic small molecules for heart regeneration
The current treatment for heart failure is transplantation. Unfortunately, only about 30% of patients survive until they can get new hearts. The major problem in cardiac dysfunction is the death of muscle cells after a heart attack. Cardiac regeneration is the key to a non-transplantation form of treatment for heart failure following myocardial infarctions. Use of novel small molecules could help to fight one of the deadliest diseases of modern times.
The search for small molecules that enhance myocardial repair has led to the discovery of a number of potential cardiogenic small molecules. Stem cell therapies for heart regeneration rely on understanding how cells differentiate into cardiac genes from stem cells. Researchers identified small molecules that involve the activation of a cardiac gene called Nkx2.5 in various mouse stem cells, including human mobilized peripheral blood cells. This family of small molecules, called sulfonylhydrazone (Shz), was tested in bone marrow cells and transplanted into rat hearts. This procedure improved heart function after cardiac injuries. 
Fighting cancer using small molecules
Some cancers are known to depend on certain genes for their survival. Pancreatic and a particular lung cancer known as non-small cell lung cancer are particularly dependent on TBK-1 activity for growth. Researchers believe that a number of lung and pancreas cancer patients would benefit from the inhibition of TBK-1 activity. The researchers tested about 250,000 compounds for their effectiveness at fighting tumors in mice. Three and half years of investigation led to the discovery of a highly effective compound called 6-aminopyrazolopyrimidine. This small compound inhibited the activity of TBK-1 by about 50 percent in lung cancer and pancreatic cancer tissue cultures, resulting in a reduction of cancer growth.  This is an important finding for the future of fighting cancer, as this could potentially turn off a gene that cancer cells hijack to survive. Though it happened to be effective in reaching different parts of a mouse’s tumor, researchers are not yet sure whether it will penetrate solid tumors in a human body.
Quest for drug sensitizers: microRNA inhibitors            
MicroRNAs are non-coding small RNAs that regulate protein expression. These RNAs form tiny RNA strands that make complexes with proteins and target another mRNA to negatively regulate its translation (its generation of protein). MiRNAs are involved in various cellular pathways, and a miRNA can elicit multiple effects in a cell. 
Aberrant microRNA expression in cancer has been well studied. MicroRNAs are involved in tumor progression and metastasis through various mechanisms involving migration, invasion, cell proliferation, angiogenesis, and apoptosis (cell death). MicroRNAs are thought to be potential therapeutic targets for personalized cancer treatments. Different cancer types and patients demonstrate different levels of response/resistance to chemotherapies. This resistance could be correlated with the expression of a microRNA profile, and studies are being performed to increase drug sensitivity toward the treatment of cancer. For example, paclitaxel, a mitotic inhibitor used in chemotherapy, is used, along with a library of chemically synthesized inhibitors that contains all known microRNAs, in non-small cell cancer cell lines. This will hopefully identify microRNAs and microRNA inhibitors that modulate cellular viability and sensitivity.
As humans, we inevitably face diseases, some of which do not have any treatment options. To understand the epidemiology of these diseases, as well as to develop treatments, researchers have pursued different approaches.  Understanding and discovering novel compounds, especially small molecules, may help us to better treat disease in the future.

1.  Pieper et al. Discovery of a proneurogenic, neuroprotective chemical. Cell. 2010 Jul 9;142(1):39-51.
2.  Ou et al. TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation. Molecular Cell. February 2011.
3.  Sadek et al. Cardiogenic small molecules that enhance myocardial repair by stem cells. PNAS. April 22, 2008 vol. 105 no. 16.
4.  White et al. Metastamirs: a stepping stone towards improved cancer management. Nature Reviews Clinical Oncology 8, 75-84 (February 2011).
5.  Paclitaxel. Wikipedia.
6.  Schneider  et al. Small-molecule activation of neuronal cell fate. Nature Chemical Biology, 15 June 2008.
7.  Researchers create molecule that nudges nerve stem cells to mature.
8.  Small Molecule.
10.  Pertsemlidis Lab.

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