New opportunities to treat the T315I-Bcr-Abl mutant in chronic myeloid leukaemia: tyrosine kinase inhibitors and molecules that act by alternative mechanisms.
Resistance to the Bcr-Abl inhibitors approved for the treatment of chronic myeloid leukaemia (CML) may arise from different mechanisms, including Bcr-Abl amino acid mutations, gene amplification and mechanisms independent of Bcr-Abl. The T315I mutation at the gatekeeper residue is very frequent in advanced phases of the disease and is one of the main causes of resistance, disrupting important contact points between the inhibitors and the enzyme. Different strategies have been implemented to overcome this resistance, including the synthesis of new Bcr-Abl ATPcompetitive or non-ATP-competitive inhibitors, dual Aurora/Bcr-Abl inhibitors and multi-targeted kinase inhibitors. An alternative approach is the use of other compounds that do not bind directly to the Bcr-Abl protein; instead, these molecules act on several downstream pathways, regulated by or linked in different ways to Bcr-Abl, that lead to the malignant transformation of the cells. For this reason, farnesyl transferase inhibitors, MAPK inhibitors, Rac guanosine triphosphatase inhibitors, PI3K inhibitors, JAK inhibitors, Hsp90 inhibitors, mTOR inhibitors, PP2A activators and apoptosis inducers have been tested, alone or in combination with ATP-competitive inhibitors, against CML cell lines. This review discusses compounds that act on Bcr-Abl or different cell pathways and reports on the molecules active against the T315I mutation, particularly the most recent findings in this field. New molecules that are claimed by recent patents to be active on this mutation are also reported. When possible, the review will focus on medicinal chemistry in terms of chemical structure, mechanism of action and structure-activity relationships.
Schenone
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S
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV, 3, I-16132, Genova, Italy. schensil@unige.it
Brullo
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C
Botta
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M
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D001667:Binding, Competitive; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010330:Patents as Topic; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl