Defined as organic molecules with a low molecular weight (≤1000 daltons) which bind to biological macromolecules and alter their activity or function, many substances, including 90% of drugs, are classified as small molecules. These are used to interrogate biological functions and as novel therapeutics, especially in targeting cell signalling. Their low weight means they readily diffuse across cell membranes (enabling intracellular targeting) and give high oral bioavailability by easily crossing the intestinal mucosa.
Small molecules are now able to target previously ‘undruggable’ conditions, such as cancers and neurological disorders, due to leaps in imaging, prediction, and structure-based design. These combined with AI, machine learning and automation, mean small molecules could be the future of the treatment of such conditions.
With less than 25% of all proteins involved in disease being able to be targeted by conventional chemotherapeutic approaches, novel small molecule agents, such as those developed by AstraZeneca and Rgenta, are increasing that number. For such biopharmaceutical advances to be made, the key steps are target discovery, mechanism of action identification and drug optimisation for potency.
KRAS, the most commonly mutated protein in cancers, acts as a key switch in cell proliferation and were thought untargetable until 2013. A new combination of a Bioluminescence Resonance Energy Transfer (BRET) assay and NMR-spectroscopy enabled KRAS(G12C) targeting and could discover other small molecule targets. However, it is not a complete success as some mutants (such as KRAS(G12D)) are still considered ‘undruggable’.
Two of the hallmarks of cancer are the ability to override the normal physiological restraints on cell growth and survival by deregulation of protein kinase activity. Indeed, it has been found that protein kinases are the most mutated family of genes in cancers. Eleven small molecules which act as protein kinase inhibitors have been approved as cancer treatments by the US Food and Drug Administration. Protein kinases are also implicit in neuronal development and function, giving scope for small molecule action here too. However, protein kinase inhibitors have been linked to side effects, such as pulmonary hypertension.
One such group of small molecules are tyrosine kinase inhibitors. These target growth factors to prevent the formation of new blood vessels within a tumour, which, as another hallmark of cancer, slows growth and constrains tumour size. In breast cancer, tyrosine kinase inhibitors are used as an alternative to monoclonal antibodies which target the epidermal growth factor receptor, as these have problems such as cardiotoxicity, and cannot be given orally.
Poly-ADP-ribose polymerase (PARP) inhibitors represent another type of small molecule which have the potential in targeting cancers and neurological disorders. PARPs have various roles within cells, from DNA repair to the unfolded protein response, making them a key target to regulate cancer cell replication. PARP inhibitors have uses in breast and ovarian cancers with BRCA1/2 mutations and overexpression of PARP1 has been implicated in various neurological disorders. However, these molecules are poorly understood, and so research is ongoing as to how targeting these molecules could benefit patients.
Due to the nature of protein kinases, and other biological macromolecules, one of the inherent issues with inhibitors to these molecules is selectivity. The selectivity of some small molecules (such as PARPs) is sometimes hard to define. The targeted nature of these drugs also means that they are only effective in a limited proportion of patients.
Another issue in developing such targeted therapy is overcoming the inevitable resistance which develops within the disease proteins, most often through gene mutations. One example of a successful instance of this is by using another drug to mitigate the resistance. For example, INK4 protein decreases resistance to CDK4/6 kinase inhibitors in breast cancers. Other ways of reducing resistance are by using multi-target agents or hybrids combined with more established therapies. A more holistic approach to resistance is to try to find new targets for anti-cancer drugs, such as micro-RNAs or RNA m6A methylation-related proteins.
For the patients of currently ‘undruggable’ diseases, small molecules provide hope, however, the development of such drugs is a long and difficult process. Even when it is developed, the lifespan of a small molecule’s therapeutic usage can be drastically shortened by resistance, presenting another barrier to innovation. However, as cheaper and simpler alternatives to conventional treatments such as monoclonal antibodies, and with advanced technologies such as computer-aided drug design, structural biology, and combinatorial chemistry, small molecule drugs are surely ones to watch.
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Small molecules are now able to target previously ‘undruggable’ conditions, such as cancers and neurological disorders, I discuss how we got here and what it means for the market. Click to read more.
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