The Development of BTK Inhibitors: A Five-Year Update

Abstract

Bruton’s tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “BTK” and “BTK inhibitors” as keywords.

Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton’s Tyrosine Kinase for the Treatment of Lymphoma

“…With the model molecule toolkit in hand, we were curious to determine whether the “linker + E3 ligase ligand” in model molecules can facilitate the oral absorption of the compounds bearing BTK protein ligands. Although covalent BTK inhibitors present high binding affinity with BTK protein, studies have highlighted a potential caveat for covalent-based BTK-PROTACs, − and the relatively low degradation activity and poor selectivity of covalent BTK-PROTACs led us to choose a reversible or noncovalent strategy. Considering a transient interaction with the POI is enough for PROTAC-mediated ubiquitination, the ibrutinib noncovalent region (without the acrylamide) was employed as the BTK ligand.…”

“…The synthesis of intermediates 48 is outlined in Scheme 7. Intermediate 45 was prepared from intermediate 28 through amino nucleophilic substitution (44) and Boc-protection. Next, nucleophilic substitution with TsCl (46) and 22b (47) successively and Boc-deprotection afforded compound 48.…”

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

“…Of the three, ibrutinib is the most potent BTK inhibitor, followed by zanubrutinib and acalabrutinib, while acalabrutinib is the most selective, followed by zanubrutinib and ibrutinib [ 16 , 17 ]. Recently, several irreversible BTKis have been developed and are under clinical investigation ( Table 1 ) [ 6 , 18 ]. These drugs inhibit BTK activity by irreversible covalent binding with high affinity to the same cysteine 481 in BTK as ibrutinib.…”

“…They were found to required more frequent and sustained dosing but have less off-target effects on other kinases. Reversible inhibitors seem to be more effective in the treatment of autoimmune diseases such as RA, different types of MS, GVHD, and SLE [ 18 ]. However, while clinical trials with these drugs are promising, they are less advanced than those with irreversible BTK inhibitors.…”

New drugs for multiple sclerosis: new treatment algorithms

“…B-cell receptor activation results in intracellular signaling through this kinase with downstream transcriptional regulation governing diverse processes including chemotaxis, trafficking, adhesion, maturation, antibody production and cytokine secretion [19]. Inhibition of BTKs is a proved treatment for lymphoma and is under investigation in diverse autoimmune disorders [20]. As small molecules, BTK inhibitors (BTKIs) could have advantages over biologics since they are less likely to trigger antibody mediated responses and have the potential for CNS penetrance.…”