Bruton’s tyrosine kinase (BTK) is a protein inside cells that plays a significant role in the growth and survival of B-cells, a type of white blood cell in the immune system. In certain cancers, particularly those affecting B-cells, BTK can become overactive, contributing to the uncontrolled proliferation of malignant cells.
BTK degraders represent a newer class of targeted therapies designed to address this issue by eliminating the BTK protein from cancer cells. Instead of simply blocking BTK’s activity, these drugs work by prompting the cell to dispose of the protein entirely. This approach holds promise for treating conditions where BTK’s activity is a driving factor in disease progression.
The Mechanism of BTK Degraders
BTK degraders operate through proteolysis-targeting chimeras (PROTACs). These PROTACs are bifunctional molecules, meaning they have two distinct ends that perform different tasks. One end is engineered to specifically recognize and bind to the BTK protein, acting as a “BTK hook”.
The other end binds to a component of the cell’s natural protein disposal system, an E3 ubiquitin ligase, such as cereblon. Once the PROTAC binds to both BTK and the E3 ubiquitin ligase, it acts as a molecular matchmaker, bringing the two together. This close proximity enables the E3 ligase to attach a small protein tag called ubiquitin onto the BTK protein.
The attachment of multiple ubiquitin tags forms a chain, signaling to the cell’s proteasome that the BTK protein is marked for destruction. The proteasome then breaks down the ubiquitinated BTK protein into smaller, inactive fragments, effectively removing it from the cell. This catalytic process means a single degrader molecule can facilitate the destruction of many BTK proteins, leading to a reduction in BTK levels within the cell.
How Degraders Differ From Inhibitors
BTK degraders differ from traditional BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib). BTK inhibitors work by binding to the active site of the BTK protein, where its enzymatic activity occurs. By occupying this site, inhibitors prevent BTK from performing its signaling functions, effectively “turning off” the protein’s activity without physically removing it from the cell.
This mechanism is comparable to removing the key from a car’s ignition; the car remains present, but it cannot run. In contrast, BTK degraders physically eliminate the entire BTK protein from the cell. This difference results in a more sustained reduction of BTK levels.
Rather than just blocking activity, degraders are akin to having the entire car towed away and scrapped. This results in an irreversible effect where new BTK protein must be produced by the cell to restore function. The complete removal of the protein by degraders can offer a more sustained therapeutic effect compared to the transient inhibition provided by traditional inhibitors.
Therapeutic Applications
BTK degraders are being developed for B-cell malignancies, cancers originating from B-lymphocytes. These diseases often rely on BTK signaling for their growth and survival.
B-Cell Malignancies
Chronic lymphocytic leukemia (CLL)
Mantle cell lymphoma (MCL)
Waldenström’s macroglobulinemia (WM)
Marginal zone lymphoma (MZL)
Diffuse large B-cell lymphoma (DLBCL)
Several novel agents are currently in early-phase clinical trials, showing promising results in heavily pretreated patients. Beyond cancer, BTK is also involved in various immune cell functions, leading to the exploration of these drugs for certain autoimmune diseases where BTK hyperactivity contributes to inflammation.
Overcoming Drug Resistance
BTK degraders can address drug resistance that often develops with traditional BTK inhibitors. Cancer cells can acquire mutations in the BTK protein, which alter its structure and prevent inhibitor drugs from binding effectively. A common example is the C481S mutation, where a cysteine amino acid is replaced by serine.
This mutation disrupts the covalent bond formed by many inhibitors, making them ineffective and leading to treatment failure. Since BTK degraders bind to different regions of the BTK protein and trigger its complete removal, they can often remain effective even when these resistance mutations are present. This capability extends to various BTK mutations, including C481S, which can arise from both covalent and non-covalent BTK inhibitors.
BTK degraders can even overcome resistance from “kinase-dead” BTK mutants. These mutants, despite lacking enzymatic activity, can still promote B-cell activation through a scaffolding function. By degrading the entire protein, degraders dismantle this scaffolding, offering a new therapeutic option for patients whose cancers have become resistant to existing treatments.