2.4.3 CG-806
The dual BTK/SYK inhibitor, CG-806 (luxeptinib), downregulates the expression of the anti-apoptotic proteins Mcl-1 and Bcl-xl, inhibits the Akt/mTOR signaling pathway, and mitochondrial inner membrane depolarization, accompanied by metabolic reorganization of glycolysis, thereby inducing apoptosis in MCL cells64. the BCR signaling pathway can drive NFκB, induce Bcl-2 protein expression, and Bcl-2 is a key factor in BCR cross-linking, and BCR cross-linking, which activates the Akt/mTOR pathway, can also promote the interaction between SRC family kinases (e.g. LYN) and CD79A/B and activate splenic tyrosine kinase (SYK). Elana Thieme et al 64 showed that the dual BTK/SYK inhibitor CG-806 interferes with the BCR signaling pathway in the above manner. The loss of BAX, an activator of apoptosis, makes CG-806 anti-apoptotic. They also found that Bcl-2 and MOMP bind to CG-806, suggesting that Bcl-2 and MOMP play an important role in the induction of apoptosis by CG-806. Inactivation of type I interferons and cell cycle control pathways, as well as Wnt/β-linked protein and mTOR signaling pathways, promote CG-806 resistance. Downregulation of NFκB pathway was associated with increased BCL2/BAX expression, NFKBIA is a negative regulator of NFκB signaling, and CG-806 became less effective in treating MCL cells after knockdown of NFκB and BAX. The above confirms that the NFκB pathway and the Bcl-2 family network play a very important role in BTK / SYK dual inhibition.