Specificity inhibitor of leukaemia bcr/abl fusion gene mRNA

Abstract

The invention discloses a leucocythemia bcr / abl fusion gene targeting micromolecule inhibitor. The compound is obtained through the reaction and salt forming of 2 Beta-(4'-methyl-1'- piperazine group)-3 Alpha-hydroxy-5 Alpha- steride -17-ketone and caffeic acid. The compound salt effectively suppresses the synthesis of mRNA of the bcr / abl fusion gene to inhibite the expression of BCR / ABL protein to inhibite the activity of protein-tyrosine kinase consequently to finally suppress the growth of leucocythemia cells. The compound salt is developed and is expected to be a bcr / abl fusion gene targeting therapeutic agent in the true sense. Therefore, the leucocythemia bcr / abl fusion gene targeting micromolecule inhibitor provides a brand new chemical entity for treating the CML and Ph positive (Ph+) chronic granulocytic leukemia and Ph positive (Ph<+>) acute lymphoblastic leukemia.

Description

technical field [0001] The present invention relates to a leukemia gene targeting therapy agent, in particular to caffeates of steroid derivatives. Background technique [0002] Chronic myeloid leukemia (CML) is one of the earliest leukemias discovered by human beings. The incidence rate is about 2 / 100,000 of the population, and its annual incidence rate is on the rise. The research and treatment of CML are divided into several landmark stages: In 1960, Nowell and Hungerford discovered the Ph chromosome. In 1972, Rowley discovered that the Ph chromosome was caused by the reciprocal translocation of the abl and bcr genes between chromosomes 9 and 22. In 1982, Klein et al. confirmed the existence of fusion gene bcr / abl, almost in more than 95% of CML cases, bcr / abl fusion gene exists. In 1990, Daley et al. confirmed that introducing the bcr / abl fusion gene into mice could induce CML-like diseases, thus locking the bcr / abl fusion gene as the pathogenic gene of CML. In 1996, ...

AI Technical Summary

Problems solved by technology

With the application of this drug, the main problem exposed is the generation of drug resistance. The main reason is that the point mutation of BCR / ABL protein is usually located in the active region of tyrosine kinase, so that Imatinib cannot effectively bind to the kinase site Inhibit its activity, resulting in about 70% leukemia relapse rate

At present, in order to overcome this shortcoming, the second-generation and third-generation tyrosine kinase inhibitors have been developed one after another, but they are all aimed at the binding site of BCR / ABL protein, and no real bcr / abl fusion gene has been seen yet. Targeted inhibitors, that is, directly inhibit the expression of bcr / abl mRNA fusion gene, and then inhibit the expression of BCR / ABL protein

Although it has been reported in the literature that siRNA can inhibit the expression of bcr / abl mRNA fusion gene, its stability in vivo is particularly important as a drug, and siRNA is limited in its development as a drug due to its poor stability

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