Sunitinib kinase activation

Gastrointestinal stromal tumor (GIST) Mutation c-KIT c-KIT(tyrosi ne-kinase activity) Imatinib, Dasatinib, Sunitinib... 

Sunitinib maleate is the first in a new class of orally active multitargeted tyrosine kinases launched for the treatment of metastastic cancers. 

Nexavar, A.49). Sorafenib inhibits VEGFR, PDGFR, and another protein kinase called Rafl kinase. Both sunitinib and sorafenib are active against some cancers of the kidney. Sunitinib is indicated against cancers of the gastrointestinal system as well, while sorafenib affects certain liver cancers. 

In summary, sunitinib maleate (1) is a multitargeted receptor tyrosine kinase inhibitor with potent anti-angiogenic and antitumor activity. It is approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors, and is currently undergoing clinical trials for a number of additional malignancies. The discovery synthesis of 1 along with its process development approaches were described in this chapter. 

Context-dependent functionalities introduce a risk of toxicity in molecular target therapy [4-7], For example, the constitutively active chimera Bcr-ABL kinase is a clinical target for treating chronic myeloid leukemia (CML), as evidenced by the success of the KI imatinib (Gleevec) [18], but ABL inhibition in cardiomyocytes (off-target cells in CML treatment) may introduce a cardiotoxicity risk [5-7], as shown in Fig. 12.1. This risk is more pronounced for promiscuous KIs like sunitinib [5, 8],... 

Inhibitor resistance mutants have also been identified in tumors from patients with gastrointestinal stromal tumors (GISTs).38 These tumors are driven by activating mutations of KIT and PDGFRa receptor tyrosine kinases.39 Both imatinib and sunitinib are indicated to treat surgically inoperable GISTs. However, complete responses are rare and many patients go on to develop secondary resistance.40... 

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