Directly targeting BAX for drug discovery:Therapeutic opportunities and challenges

For over two decades,the development of B-cell lymphoma-2(Bcl-2)family therapeutics has primarily focused on anti-apoptotic proteins,resulting in the first-in-class drugs called BH3 mimetics,especially for Bcl-2 inhibitor Venetoclax.The pro-apoptotic protein Bcl-2-associated X protein(BAX)plays a crucial role as the executioner protein of the mitochondrial regulated cell death,contributing to organismal development,tissue homeostasis,and immunity.The dysregulation of BAX is closely associated with the onset and progression of diseases characterized by pathologic cell survival or death,such as cancer,neurodegeneration,and heart failure.In addition to conducting thorough investigations into the physiological modulation of BAX,research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX,as well as diverse all-molecule BAX modulators.This review presents recent advancements in elucidating the physiological and pharmacological modulation of BAX and in identifying potentially druggable binding sites on BAX.Furthermore,it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or conformations of BAX,offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX.

Liposome-based anchoring and core-encapsulation for combinatorial cancer therapy

Downregulated pro-apoptotic protein in cancer cells compromises the chemotherapy by a cytotoxic drug.Here,we report co-delivery of a pro-apoptotic protein,caspase 3(Cas 3),and cytotoxic agent,oridonin(ORD),for synergistic cancer treatment,using a method of liposome-based anchoring and core encapsulation.First,ORD is modified with hyaluronic acid(HA)to improve its solubility.Then,the targeted co-delivery system is prepared by assembling the conjugate HA-ORD onto the Cas 3-loaded liposomes,which the surface HA can target the CD44 receptor on cancer cells.In vitro,the co-loaded liposomes(120 nm)are specifically taken up by 4T1 cells and endow a 1.5-fold increase of Cas 3.After intravenous injection into the tumor-bearing mice,the liposomes accumulate in the tumor with high efficacy and significantly inhibit tumor growth via promoting apoptosis and anti-proliferation of cancer cells.Mechanistically,the co-delivery works synergistically by upregulating the activated Cas form,cleaved-Cas 3.