Journal: Signal Transduction and Targeted Therapy

Article Title: The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

doi: 10.1038/s41392-025-02176-0

Figure Lengend Snippet: Milestones in the development of BH3-mimetics . a Overview of the anti-apoptotic BCL2 family proteins containing the BH domains and alpha helical structures α1-α9. b General interaction pattern within the BCL2 family, with the anti-apoptotic proteins inhibiting the pore-forming pro-apoptotic proteins BAX and BAK. The BH3-only proteins inhibit the anti-apoptotic BCL2 proteins and may also induce direct activation of BAX and BAK. c Timeline illustrating milestones and achievements in the discovery of BCL2 proteins and the development of BH3-mimetics. a and b Created in BioRender

Article Snippet: Due to its function in platelet survival, packaging into nanoparticles may be particularly important for BH3-mimetics targeting BCL-X L . To this end, the dual BCL2/BCL-X L inhibitor AZD4320 has been further developed as a PEGylated poly-lysine dendrimer conjugate.

Techniques: Activation Assay

Journal: Signal Transduction and Targeted Therapy

Article Title: The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

doi: 10.1038/s41392-025-02176-0

Figure Lengend Snippet: Overview of the BCL2 family and the regulation of cytochrome c release . a In unstressed healthy cells, several mechanisms, including canonical and non-canonical functions of BCL2 family members, prevent MOMP and release of cytochrome c from mitochondria, including the retrotranslocation of BAX/BAK and the limited availability of BH3-only proteins at mitochondrial membranes and preventing mitochondrial Ca 2+ overload. b Upon cellular stress, BH3-only proteins become available at the mitochondria and facilitate BAX/BAK oligomerization, leading to MOMP. This is also facilitated by increased Ca 2+ signaling including Ca 2+ transfers from ER stores towards mitochondria. Created in BioRender

Article Snippet: Due to its function in platelet survival, packaging into nanoparticles may be particularly important for BH3-mimetics targeting BCL-X L . To this end, the dual BCL2/BCL-X L inhibitor AZD4320 has been further developed as a PEGylated poly-lysine dendrimer conjugate.

Techniques:

Journal: Signal Transduction and Targeted Therapy

Article Title: The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

doi: 10.1038/s41392-025-02176-0

Figure Lengend Snippet: Genetic alterations in cancer . Analysis of genetic modifications involving BCL2 , BCL2L1 and MCL1 using cBioportal – was performed. Four main pan-cancer studies using targeted deep sequencing and encompassing 71,060 samples were selected (MSK-IMPACT, Cancer Therapy and Clonal Hematopoesis, China Pan-Cancer and MSK MetTropism ) and analyzed for genetic alterations involving BCL2 , BCL2L1 or MCL1 in different cancer types. Thresholds were set for 100 samples / cancer type and a minimal frequency of 0.5%

Article Snippet: Due to its function in platelet survival, packaging into nanoparticles may be particularly important for BH3-mimetics targeting BCL-X L . To this end, the dual BCL2/BCL-X L inhibitor AZD4320 has been further developed as a PEGylated poly-lysine dendrimer conjugate.

Techniques: Sequencing

Journal: Signal Transduction and Targeted Therapy

Article Title: The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

doi: 10.1038/s41392-025-02176-0

Figure Lengend Snippet: BCL2 family dependencies in cancer . Boxplots depicting the Chronos dependency scores of BCL2 , BCL2L1 and MCL1 of cancer cell lines according to the DepMap data. Cancer subtypes (primary disease) with data available for n ≥ 5 cell lines were included. If multiple subtypes belonged to one lineage, the lineage was color-coded, the rest are shown in black

Article Snippet: Due to its function in platelet survival, packaging into nanoparticles may be particularly important for BH3-mimetics targeting BCL-X L . To this end, the dual BCL2/BCL-X L inhibitor AZD4320 has been further developed as a PEGylated poly-lysine dendrimer conjugate.

Techniques:

Journal: Signal Transduction and Targeted Therapy

Article Title: The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

doi: 10.1038/s41392-025-02176-0

Figure Lengend Snippet: Clinically developed BH3-mimetics . a Overview of current clinically tested BH3-mimetics targeting BCL2, BCL-X L , MCL1 or multiple anti-apoptotic BCL2 proteins (created in Biorender). b Hydrophobic pockets P1, P2, P3 and P4 mapped onto the surface of the BCL2 structure (PDB-id: 1G5M ). c Zoom into SS55746, navitoclax, venetoclax or sonrotoclax bound to BCL2 (PDB-id: 6GL8, PDB-id: 4LVT, PDB-id: 6O0K, PDB-id: 8HOG). d Overlay of venetoclax bound to BCL2 (light grey) and BCL2-G101V (yellow). Mutation of glycine 101 (light grey spheres) to valine (yellow spheres) effects conformational change (indicated by black arrow) of the adjacent E152 (side chains as sticks in light grey and yellow, respectively), pushing it towards the chlorine (green) of venetoclax and slightly displacing it. (PDBids: 6O0K and 6O0L ). e 2D sketches of inhibitors shown in B-E, and pelcitoclax and lisaftoclax

Article Snippet: Due to its function in platelet survival, packaging into nanoparticles may be particularly important for BH3-mimetics targeting BCL-X L . To this end, the dual BCL2/BCL-X L inhibitor AZD4320 has been further developed as a PEGylated poly-lysine dendrimer conjugate.

Techniques: Mutagenesis

Journal: Signal Transduction and Targeted Therapy

Article Title: The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

doi: 10.1038/s41392-025-02176-0

Figure Lengend Snippet: Prediction of BH3-mimetic responses . Linear regression analyses between cancer cell line response to BH3-mimetics from the PRISM Drug Repurposing Library and BCL2 RNA interference (green), BCL2 dependence score (pink) and BCL2 gene expression (blue). a Linear regression analyses between response to ABT-199 (venetoclax) and BCL2 (myeloid and lymphoid malignancies were not included in PRISM repurposing screening for ABT-199). b Linear regression analyses between response to ABT-263 (navitoclax) and BCL2. c Linear regression analyses between response to ABT-263 (navitoclax) and BCL2L1/BCL-X L . d Linear regression analyses between response to S63845 and MCL1. The most significant correlation is a negative one between BCL2L1 expression and navitoclax response ( c ), however the R-squared value is only 0.06

Article Snippet: Due to its function in platelet survival, packaging into nanoparticles may be particularly important for BH3-mimetics targeting BCL-X L . To this end, the dual BCL2/BCL-X L inhibitor AZD4320 has been further developed as a PEGylated poly-lysine dendrimer conjugate.

Techniques: Gene Expression, Expressing

Journal: Signal Transduction and Targeted Therapy

Article Title: The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

doi: 10.1038/s41392-025-02176-0

Figure Lengend Snippet: BH3-mimetics in clinical development

Article Snippet: Due to its function in platelet survival, packaging into nanoparticles may be particularly important for BH3-mimetics targeting BCL-X L . To this end, the dual BCL2/BCL-X L inhibitor AZD4320 has been further developed as a PEGylated poly-lysine dendrimer conjugate.

Techniques:

Journal: Signal Transduction and Targeted Therapy

Article Title: The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

doi: 10.1038/s41392-025-02176-0

Figure Lengend Snippet: BCL2 protein targeting PROTACs and SNIPERs

Article Snippet: Due to its function in platelet survival, packaging into nanoparticles may be particularly important for BH3-mimetics targeting BCL-X L . To this end, the dual BCL2/BCL-X L inhibitor AZD4320 has been further developed as a PEGylated poly-lysine dendrimer conjugate.

Techniques: Modification