Molecular building blocks, also known as organic building blocks, are functionalized molecules that serve as the foundational components for organic synthesis. Utilized for bottom-up modular assembly, they enable the construction of molecular architectures such as supramolecular complexes, metal-organic frameworks, organic molecular constructs, and nanoparticles. These building blocks can be grouped and identified according to their chemical structures such as heterocyclic and fluorinated building blocks.

Molecular building blocks allow chemists to streamline drug discovery through synthesis. In this article, we will examine the benefits of molecular building blocks in drug development, using JAK inhibitors as a case study to demonstrate their potential in curing diseases.

The Biology Behind JAK Inhibitors

The Janus kinase (JAK) - signal transducer and activator of transcription (STAT) signaling pathway plays a key role in various cellular processes such as cell division, apoptosis, inflammatory reactions, and carcinogenesis. The activation of the JAK-STAT signaling pathway begins when extracellular ligands, like cytokines, bind to transmembrane type I and II cytokine receptors, leading to receptor dimerization.

As a result, JAKs become accessible to the dimeric receptor, causing autophosphorylation. The activated JAKs then phosphorylate their receptors, allowing STATs to recognize them. This facilitates STAT phosphorylation by JAKs, and subsequently, the activated STATs form dimers and translocate to the cell nucleus. Finally, STATs bind to specific DNA regions, triggering the transcription of target genes. Given the significant role of the JAK-STAT signaling pathway in immune response, JAKs have become attractive drug targets for inhibitors that block cytokine signaling.

JAK Inhibitors and Drug Development

To date, several JAK inhibitors have been approved, starting with Ruxolitinib in 2011. Generally, JAKs consist of seven JAK homology (JH1-7) domains with the JH1 (colored in magenta) and JH2 (colored in marine) domains directly associated with catalytic function as kinases.

Approved JAK inhibitors typically bind competitively to the ATP-binding site. When visualizing the binding patterns of JAK1 and JAK2 with certain tinib-related ligands, it is evident that these molecular building blocks insert into the same pockets of JAKs. For example, the following image shows the approved drugs Ruxolitinib binding with JAK2 JH1 domain (PDB 6WTN), Tofacitinib binding with JAK2 (PDB 3FUP), and Baricitinib binding with JAK2 JH1 domain (PDB 6VN8) - the molecular building block inserts into the same pockets of JAKs. This is also the case with investigational compounds (PDB 5KHX, whose ligand is the substructure of Abrocitinib; PDB 6BBU; PDB 6SM8). As biology and chemistry abide by the principle that 'structure determines function', the molecular moiety provided by CAS No. 3680-69-1 mimicks the structure of adenosine molecule and therefore it inserts into the pockets of JAK1 and JAK2, occupying the space usually reserved for ATP and disrupting JAKs' cellular function. 

Conclusion

Therefore, medicinal chemists can cleverly design and refine potential therapeutic drug chemical structures while maintaining the moiety provided by CAS No. 3680-69-1. Molecular building blocks play a crucial role in drug discovery and development, as their ability to streamline the drug design process can greatly benefit global drug companies.

References

Roskoski, R. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res 111, 784–803 (2016).

Kwon, S. Molecular dissection of Janus kinases as drug targets for inflammatory diseases. Front Immunol 13, 1075192 (2022).