Dasatinib [BMS 354825] is an orally active, small molecule, dual inhibitor of both SRC and ABL kinases that is under development with Bristol-Myers Squibb for the treatment of patients with chronic myelogenous leukaemia (CML) and imatinib-acquired resistance/intolerance. It’s used for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia with resistance or intolerance to prior therapy. Also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. While imatinib remains a frontline therapy for CML, patients with advanced disease frequently develop resistance to imatinib therapy through multiple mechanisms. Dasatinib is also undergoing preclinical evaluation for its potential as a therapy against multiple myeloma. Bristol-Myers Squibb has a composition-of-matter patent covering this research approach that will expire in 2020. Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.

MKC-1 is an orally available cell cycle inhibitor with downstream targets that include tubulin and the importin-β family. MKC-1 has shown broad antitumor activity in preclinical models. MKC-1 and its metabolites inhibit tubulin polymerization, blocking the formation of the mitotic spindle, which may result in cell cycle arrest at the G2/M phase and apoptosis. In addition, this agent has been shown to inhibit the activities of the oncogenic kinase Akt, the mTOR pathway, and importin-beta, a protein essential to the transport of other proteins from the cytosol into the nucleus. MKC-1 had been in phase II clinical trials for the treatment of ovarian cancer, endometrial cancer, pancreatic cancer and breast cancer. This compound was originally discovered by Roche, then licensed to EntreMed (now CASI Pharmaceuticals) the exclusive worldwide rights to develop and commercialize. However, no recent development has been reported.

XL-228 is a third generation inhibitor of Abl that shows efficacy in a variety of cell lines, including those exhibiting T315I mutations. XL-228, a tyrosine kinase inhibitor, is involved in binding to and inhibiting the activities of multiple tyrosine kinases, such as the insulin-like growth factor 1 receptor (IGF1R), Src tyrosine kinase, and Bcr-Abl tyrosine kinase. Blockade of these kinases may result in the inhibition of tumor angiogenesis, cell proliferation, and metastasis. XL-228 is a multitargeted protein kinase inhibitor targeting IGF1R, the aurora kinases, IGF-1R, cSrc, BCR/Abl and SRC kinases. XL-228 displays anticancer chemotherapeutic activity and it was in clinical trials as a potential treatment for chronic myelogenous leukemia (CML). On 22 Feb 2011 phase I clinical studies for chronic myeloid leukaemia and cancer in USA were discontinued.

Dasatinib [BMS 354825] is an orally active, small molecule, dual inhibitor of both SRC and ABL kinases that is under development with Bristol-Myers Squibb for the treatment of patients with chronic myelogenous leukaemia (CML) and imatinib-acquired resistance/intolerance. It’s used for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia with resistance or intolerance to prior therapy. Also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. While imatinib remains a frontline therapy for CML, patients with advanced disease frequently develop resistance to imatinib therapy through multiple mechanisms. Dasatinib is also undergoing preclinical evaluation for its potential as a therapy against multiple myeloma. Bristol-Myers Squibb has a composition-of-matter patent covering this research approach that will expire in 2020. Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.

Dasatinib [BMS 354825] is an orally active, small molecule, dual inhibitor of both SRC and ABL kinases that is under development with Bristol-Myers Squibb for the treatment of patients with chronic myelogenous leukaemia (CML) and imatinib-acquired resistance/intolerance. It’s used for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia with resistance or intolerance to prior therapy. Also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. While imatinib remains a frontline therapy for CML, patients with advanced disease frequently develop resistance to imatinib therapy through multiple mechanisms. Dasatinib is also undergoing preclinical evaluation for its potential as a therapy against multiple myeloma. Bristol-Myers Squibb has a composition-of-matter patent covering this research approach that will expire in 2020. Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.