Danusertib (formerly PHA-739358)--a novel combined pan-Aurora kinases and third generation Bcr-Abl tyrosine kinase inhibitor.
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Danusertib (formerly PHA-739358)--a novel combined pan-Aurora kinases and third generation Bcr-Abl tyrosine kinase inhibitor. / Gontarewicz, Artur; Brümmendorf, Tim.
In: Recent Results Cancer Res, Vol. 184, 2010, p. 199-214.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Danusertib (formerly PHA-739358)--a novel combined pan-Aurora kinases and third generation Bcr-Abl tyrosine kinase inhibitor.
AU - Gontarewicz, Artur
AU - Brümmendorf, Tim
PY - 2010
Y1 - 2010
N2 - The Aurora kinases belong to a family of highly conserved serine/threonine protein kinases. They play an essential role as key mitotic regulators, controlling entry into mitosis, centrosome function, chromosome assembly, and segregation. As many other regulators of mitosis, Aurora kinases are frequently found to be aberrantly overexpressed in cancer cells. Therefore, these proteins have become an attractive target for the development of new anticancer therapies. In fact, several small-molecule inhibitors of Aurora kinases have already been developed and some of them have shown promising clinical efficacy in a number of human tumors in Phase I and II clinical trials. Among those, one of the most advanced clinical compound currently is Danusertib (formerly PHA-739358), which exhibits inhibitory activity against all known Aurora kinases as well as other cancer-relevant kinases such as the Bcr-Abl tyrosine kinase, including its multidrug-resistant T315I mutant. This mutation is responsible for up to 25% of all clinically observed resistances in CML patients undergoing Imatinib therapy. However, this particular mutation is predicted to play an even more important clinical role in the future, since in addition to Imatinib, it also confers resistance to second-generation Bcr-Abl inhibitors such as Nilotinib, Dasatinib, and Bosutinib. Therefore, combined Aurora and Bcr-Abl inhibition (the latter including high-grade resistance conferring mutations) with compounds such as Danusertib represents a promising new strategy for treatment of Bcr-Abl positive leukemias, especially those in second and third line of treatment.
AB - The Aurora kinases belong to a family of highly conserved serine/threonine protein kinases. They play an essential role as key mitotic regulators, controlling entry into mitosis, centrosome function, chromosome assembly, and segregation. As many other regulators of mitosis, Aurora kinases are frequently found to be aberrantly overexpressed in cancer cells. Therefore, these proteins have become an attractive target for the development of new anticancer therapies. In fact, several small-molecule inhibitors of Aurora kinases have already been developed and some of them have shown promising clinical efficacy in a number of human tumors in Phase I and II clinical trials. Among those, one of the most advanced clinical compound currently is Danusertib (formerly PHA-739358), which exhibits inhibitory activity against all known Aurora kinases as well as other cancer-relevant kinases such as the Bcr-Abl tyrosine kinase, including its multidrug-resistant T315I mutant. This mutation is responsible for up to 25% of all clinically observed resistances in CML patients undergoing Imatinib therapy. However, this particular mutation is predicted to play an even more important clinical role in the future, since in addition to Imatinib, it also confers resistance to second-generation Bcr-Abl inhibitors such as Nilotinib, Dasatinib, and Bosutinib. Therefore, combined Aurora and Bcr-Abl inhibition (the latter including high-grade resistance conferring mutations) with compounds such as Danusertib represents a promising new strategy for treatment of Bcr-Abl positive leukemias, especially those in second and third line of treatment.
KW - Animals
KW - Humans
KW - Clinical Trials as Topic
KW - inhibitors
KW - Benzamides pharmacology
KW - Neoplasms drug therapy
KW - Protein-Serine-Threonine Kinases antagonists
KW - Pyrazoles pharmacology
KW - Animals
KW - Humans
KW - Clinical Trials as Topic
KW - inhibitors
KW - Benzamides pharmacology
KW - Neoplasms drug therapy
KW - Protein-Serine-Threonine Kinases antagonists
KW - Pyrazoles pharmacology
M3 - SCORING: Zeitschriftenaufsatz
VL - 184
SP - 199
EP - 214
JO - Recent Results Cancer Res
JF - Recent Results Cancer Res
SN - 0080-0015
ER -