Asciminib, known by its brand name Scemblix, is a targeted therapy used to treat certain forms of cancer. It offers a different approach to inhibiting specific proteins that drive cancer growth. This oral treatment is primarily prescribed for patients with a particular type of leukemia.
The BCR-ABL1 Oncoprotein in Chronic Myeloid Leukemia
Chronic Myeloid Leukemia (CML) is a cancer of the blood and bone marrow characterized by the overproduction of white blood cells. The disease’s origin is a specific genetic abnormality. In CML patients, a chromosomal translocation occurs where a piece of chromosome 9 and a piece of chromosome 22 break off and switch places. This event creates an abnormally short chromosome 22, known as the Philadelphia chromosome.
The swapping of genetic material fuses two genes: the Breakpoint Cluster Region (BCR) gene from chromosome 22 and the Abelson murine leukemia (ABL1) gene from chromosome 9. This new BCR-ABL1 gene serves as the blueprint for an oncoprotein, a protein that can cause cancer.
The BCR-ABL1 oncoprotein is a type of enzyme called a tyrosine kinase, which functions as a signaling protein. Normal ABL1 kinase activity is tightly regulated, switching on and off as needed. However, the fusion with BCR causes the ABL1 kinase portion of the new protein to become permanently stuck in the “on” position. This constant, unregulated signaling is like a stuck gas pedal, telling the bone marrow stem cells to divide and multiply uncontrollably, leading to the characteristic features of CML.
Targeting the ABL Myristoyl Pocket
Asciminib has a distinct mechanism of action. It is a STAMP inhibitor, which stands for Specifically Targeting the ABL Myristoyl Pocket. This pocket is a natural regulatory site on the ABL1 kinase domain, separate from the enzyme’s main active site. In a healthy ABL1 protein, a fatty acid called a myristoyl group binds to this pocket, helping to hold the protein in an inactive state.
The formation of the BCR-ABL1 oncoprotein disrupts this natural self-regulation. Asciminib was designed to restore this inhibitory control. It binds directly to the myristoyl pocket on the ABL1 portion of the fusion protein. This action locks the enzyme into an inactive conformation, shutting down its signaling activity.
By binding to this allosteric site—a location other than the enzyme’s active site—asciminib mimics the natural regulatory mechanism of the ABL1 protein. This induced change prevents the oncoprotein from driving cell proliferation. The precision of targeting this unique pocket gives the drug its high selectivity.
Contrast with ATP-Competitive Tyrosine Kinase Inhibitors
Asciminib’s mechanism contrasts with previous generations of tyrosine kinase inhibitors (TKIs) used for CML, like imatinib, dasatinib, and nilotinib. These earlier drugs are ATP-competitive inhibitors. They target the active site of the BCR-ABL1 kinase, where adenosine triphosphate (ATP) binds to power the enzyme’s signaling.
Traditional TKIs work by physically blocking the ATP-binding site, preventing the enzyme from accessing its fuel source and inhibiting its activity. While effective, the ATP-binding site is a common feature in many kinases throughout the body. Although drugs like imatinib are relatively selective for BCR-ABL1, their action at this common site can lead to off-target effects.
Asciminib’s allosteric inhibition at the myristoyl pocket is a different strategy. It uses a secondary, regulatory location to achieve inactivation instead of competing with ATP at the active site. This is important for patients who develop resistance to ATP-competitive drugs. The unique binding site means asciminib can function even when the target of other TKIs has changed.
Overcoming Treatment Resistance
A challenge in the long-term management of CML is treatment resistance. The BCR-ABL1 gene can undergo further mutations that alter the oncoprotein’s structure. Many of these mutations occur within the ATP-binding site, changing its shape so that traditional TKIs can no longer bind effectively.
Because asciminib binds to the myristoyl pocket, it can circumvent this form of resistance. Its efficacy is not dependent on the shape of the ATP-binding site. This allows it to remain active against BCR-ABL1 variants resistant to other TKIs, providing an option for patients whose disease has progressed after other treatments.
This is relevant for patients with the T315I mutation, which confers broad resistance to most ATP-competitive TKIs. Asciminib’s mechanism allows it to inhibit the BCR-ABL1 kinase even when the T315I mutation is present. This ability to overcome such resistance mutations is a clinical advantage of its distinct action.