FAM119B Inhibitors

Chemical inhibitors of FAM119B operate through a variety of mechanisms that directly interfere with the protein's enzymatic activity, each engaging with different aspects of its function as a methyltransferase. S-Adenosylmethionine (SAM) is an essential methyl donor for FAM119B, and its availability is crucial for FAM119B's function. By controlling the levels of SAM or its analogs, one can modulate the activity of FAM119B. For instance, Methylthioadenosine can saturate the intracellular milieu, which may lead to a feedback inhibition of methylation processes, thereby reducing FAM119B activity. Similarly, Adenosine dialdehyde inhibits the enzyme S-adenosylhomocysteine hydrolase, increasing the levels of S-adenosylhomocysteine which competes with SAM and acts as a potent inhibitor of methyltransferases like FAM119B. 3-Deazaneplanocin A, another inhibitor of S-adenosylhomocysteine hydrolase, also elevates S-adenosylhomocysteine levels, providing a similar mechanism of inhibition. On a structural level, inhibitors such as BIX-01294 and UNC0638 that are known to target the histone methyltransferases G9a and GLP, respectively, can bind to the active sites of these enzymes due to their structural similarity to FAM119B. This suggests that they can also bind to the active site of FAM119B, disrupting its function. Chaetocin, a specific inhibitor of SUV39H1, and EPZ004777, which targets DOT1L, can inhibit FAM119B by a similar logic, as these enzymes share conserved motifs and domains with FAM119B. Such binding can obstruct the active site of FAM119B, thereby inhibiting its methylation capability. RG108 and Decitabine are both involved in DNA methylation processes. RG108, as a non-nucleoside inhibitor, can alter the conformation of the active site, while Decitabine, a cytidine analog, can be incorporated into DNA and trap DNA methyltransferases, suggesting a mechanism by which FAM119B could be similarly inhibited. Azacitidine, which incorporates into RNA, also presents a likely mechanism of inhibition of RNA methyltransferases and by analogy could affect FAM119B. Furthermore, Quercetin, a kinase inhibitor, may alter the phosphorylation states that regulate the activity of FAM119B, providing an additional avenue of functional inhibition. Each chemical, through its unique interaction with either the active site, substrate availability, or regulatory domains of FAM119B, ensures a reduction in the overall methylation activity of the protein, achieving functional inhibition.