Novel dual Src/Abl inhibitors for hematologic and solid malignancies.
BACKGROUND
c-Src and Bcr-Abl are two non-receptor or cytoplasmic tyrosine kinases (TKs) that play important roles in the development of solid and hematological malignancies. Indeed, Src is overexpressed or hyperactivated in a variety of solid tumors, while Bcr-Abl is the causative agent of chronic myeloid leukemia (CML), where Src is also involved. The two enzymes share significant sequence homology and remarkable structural resemblance.


METHODS
ATP-competitive compounds originally developed as Src inhibitors, showed to be also potent Abl inhibitors. Dasatinib, the first dual Src/Abl inhibitor approved by the US FDA in 2006 for the treatment of imatinib-resistant CML, is currently being tested in several clinical trials for the treatment of different solid tumors. SKI-606 and AZD0530 are two other important dual Src/Abl inhibitors extensively tested in animal models and in clinical trials, but not entered into therapy yet.


RESULTS
In this review we will report the latest results regarding dasatinib, SKI-606 and AZD0530, but also the knowledge on new compounds that have appeared in the literature in the last few years, including AP24163, AP24534, XL228, DC2036. We will focus on the most recent clinical trials or on preclinical studies that are in progress on these small-molecule TK inhibitors that represent a targeted therapy with high potential against cancer.


CONCLUSIONS
Molecularly targeted therapies, including the inhibition of specific TKs hyperactivated or overexpressed in many human cancers, could be less toxic than the classical non-specific cytotoxic chemotherapeutic agents; they could offer important therapeutic effects, especially if used in association with other agents such as monoclonal antibodies.
Schenone
Silvia
S
University of Genoa, Dipartimento di Scienze Farmaceutiche, Viale Benedetto VX, Genoa, Italy. schensil@unige.it
Brullo
Chiara
C
Musumeci
Francesca
F
Botta
Maurizio
M
D000814:Aniline Compounds / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000081247:CSK Tyrosine-Protein Kinase; D002986:Clinical Trials as Topic; D000069439:Dasatinib; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy*; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D014227:Triazines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D019061:src-Family Kinases
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D011804:Quinolines; D013844:Thiazoles; D014227:Triazines; C471992:bosutinib; C515233:saracatinib; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases; C000631346:CSK protein, human; D000069439:Dasatinib