Signaling Mechanism and Pharmacological Manipulation of Bcl-2 Family Proteins in Apoptosis
Bibliographic record
Abstract
Programmed cell death (apoptosis) dysregulation can drive disease pathologies in humans. Too much cell death is an unmet issue in neurodegenerative disease, is associated with decreases in tissue engraftment success, and is a hurdle in biotechnology applications. Conversely, too little cell death is partly associated with the formation of cancer and resistance to chemotherapy treatments. In a single cell, Bcl-2 family proteins orchestrate the life-or-death decision by complex interactions at the mitochondrial outer membrane. Anti-apoptotic proteins like BCL-XL can sequester activator proteins (BID), and pore-forming proteins (BAX and BAK) to keep the cell from undergoing apoptosis. Sensitizer proteins such as BAD, can bind to anti-apoptotic proteins leading to the activation of pore-forming proteins by free activator proteins. When a BAX/BAK pore is formed on the outer membrane of the mitochondria, the cell is committed to apoptosis with no return. Pro-apoptotic factors released from the mitochondrial intermembrane space trigger an apoptotic cascade. Here, I aid in the discovery of a novel inhibition mechanism at the mitochondria where homodimerized BCL-X¬L¬ can also act as the scaffold for a “trigger like” activation of a pro-apoptotic signal. Although Bcl-2 family proteins have been studied for about 40 years, we are still observing novel mechanisms, understanding the function of structural domains, and developing small molecules as future therapies. The first success in clinic to target Bcl-2 family proteins is the anti-apoptotic protein inhibitor, Venetoclax, used to treat chronic lymphocytic leukemia. The purpose of Venetoclax is to repress inhibitory proteins to cause activation of apoptosis in cancer. However, little is known about inhibiting cell death to treat disease. BAX and BAK form pores that commit the cell to death, and by blocking pore formation we can keep cells alive for longer, allowing stressed cells time to recover. Here, I aid in the development of small-molecule BAX/BAK inhibitors to save cells from an apoptotic stimulus. I found that pyrimidine or quinazoline based, FDA-approved kinase inhibitors have low-micromolar affinities for BAX and BAK. With aid from synthetic chemists, I was able to predict chemical changes that removed kinase binding while maintaining the propensity to inhibit BAX and BAK.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".