Which gene mutations does bosutinib/bosutinib mainly target?

Bosutinib is a second-generation oral tyrosine kinase inhibitor (TKI) that is widely used in the treatment of chronic myelogenous leukemia (CML), especially for patients who are resistant or intolerant to imatinib (Imatinib). It mainly inhibits the abnormal tyrosine kinase activity encoded by the BCR-ABL fusion gene, thereby preventing the abnormal proliferation of leukemia cells. It is currently one of the mainstream international treatment options.

The BCR-ABL fusion gene is the core pathogenic core of CML. It originates from the translocation of the ABL gene on chromosome 9 and the BCR gene on chromosome 22, forming the so-called "Philadelphia chromosome". The protein expressed by this fusion gene has continuously active tyrosine kinase activity and is a key factor in inducing continued division and resistance to apoptosis of leukemia cells.

The advantage of bosutinib is that it can effectively inhibit multiple mutant types of BCR-ABL kinase. It shows unique therapeutic potential especially in patients who are resistant to first-generation TKIs. Studies have shown that bosutinib has strong inhibitory ability against mutations including Y253H, E255K, F359V, F317L, etc. These mutations usually cause imatinib treatment failure. Bosutinib, through its unique binding site and mechanism, can bypass the steric obstacles caused by these mutations and maintain the stability of the binding between the drug and the target.

In addition, bosutinib also has an inhibitory effect onSRC family tyrosine kinases. This type of kinase is involved in various signaling pathways of leukemia cells, such as cell migration, proliferation and microenvironment interaction. Bosutinib's effect on them further broadens its anti-cancer spectrum.

However, bosutinib also has target limitations. The most critical thing is that it has almost no inhibitory activity against the T315I mutated BCR-ABL kinase. This mutation is located in the "gating residue" of the kinase structure and confers resistance to most TKIs, including imatinib, nilotinib, dasatinib, and bosutinib. Currently, only third-generation TKIs such as Ponatinib or new targeted therapies have clear efficacy against T315I mutation.

Reference materials:https://go.drugbank.com/drugs/DB06616