Asciminib, sold under the brand name Scemblix, is a medication used to treat Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). Asciminib is described as a "STAMP inhibitor," which means "specifically targeting the ABL myristoyl pocket." The wild-type ABL has a myristoylated N-terminus, which binds to an allosteric site, but the ABL fusion protein does not have the myristoylated domain. In the wild-type protein, when myristoylated N-terminus binds to the allosteric site, the kinase has reduced activity. Since the mutant fusion protein does not have the myristoylated N-terminus domain, it is not subject to this form of regulation, and thus the fusion protein is constitutively active. Asciminib binds to the allosteric site, resulting in an inhibition of BCR-ABL activity. This is a new kind of allosteric inhibitors, meaning that they will bind to structural pockets different from the catalytical ones. The main advantage of this medication is that it can be administer together with classical BCR-ABL inhibitors such as Imatinib which bind to the enzyme catalytic center. The combination of two drugs results on a synergistic effect that prevent the appearance of toxic and adverse reactions. This is the structure of the ABL kinase in complex with Imatinib and Asciminib determined by X-ray crystallography (PDB code: 6HD6).
#immolecular ... #molecularart ... #chronic ... #myeloid ... #leukemia ... #cancer ... #imatinib ... #allosteric ... #inhibitor .... #asciminib ... #xray
Structure of the ABL kinase in complex with both inhibitors rendered with @proteinimaging and depicted with @corelphotopaint
#immolecular ... #molecularart ... #chronic ... #myeloid ... #leukemia ... #cancer ... #imatinib ... #allosteric ... #inhibitor .... #asciminib ... #xray
Structure of the ABL kinase in complex with both inhibitors rendered with @proteinimaging and depicted with @corelphotopaint
