SB1317, a Potent and Orally Active FLT3-CDK Inhibitor with High Anti-Tumor Efficacy in Models of Hematological Malignancies

• Published in: Blood 2007-11, Vol.110 (11), p.1593-1593
• Main Authors: Goh, Kee C., Ong, Wai C., Hu, Changyong, Liang, Ai L., Stunkel, Walter, Tan, Yong C., Sangthongpitag, Kanda, Goh, Siok K., Bonday, Zahid Q., William, Anthony D., Dymock, Brian W., Kantharaj, Ethirajulu, Wood, Jeanette M.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V110.11.1593.1593

FLT3 is the most common mutated gene in acute myeloid leukemia (AML), and FLT3 mutations are strongly correlated with poor prognosis. Small-molecule inhibitors of FLT3 kinase have been evaluated in clinical trials but with limited success due to the emergence of activating mutants other than FLT3. CDK1, 2, 4 and 6 are well-established anti-cancer targets due to their direct role in cell cycle control. CDK7 and 9 are transcriptional CDKs that are emerging anti-cancer targets as a result of recent advances in the understanding of their effects on apoptotic regulators. Recent evidence suggests that the combined targeting of CDK1, 2 and 9 enhances apoptotic killing of tumor cells. Most CDK active compounds currently in clinical development do not target all of these CDKs and have poor pharmacokinetic/pharmacodynamic properties. Compounds targeting these CDKs, in addition to FLT3, may be more effective in AML and also be effective against other hematological as well as solid tumors. SB1317 is a novel potent inhibitor of FLT3 kinase (IC50 = 45 nM) and CDK2 (IC50 = 11 nM). The CDK spectrum also includes potent inhibition of CDK1 and 9 (IC50 = 19 and 10 nM respectively). SB1317 inhibits proliferation of a broad panel of tumor cell lines, and is particularly potent against the mutant FLT3-dependent AML cell line, MV4-11 (proliferation IC50 = 18 nM). SB1317 reduced phospho-Rb and phospho-FLT3 levels in MV4-11 cells in a dose-dependent manner. It induced apoptosis in MV4-11 cells as well as in primary AML cells from patients. The pharmaceutical, metabolic and pharmacokinetic properties of SB1317 render it amenable to oral dosing. In a nude mouse subcutaneous model of AML (MV4-11), SB1317 induced complete tumor regression after oral daily dosing (40 mg/kg for 21 days). In an orthotopic model of AML (HL60), SB1317 significantly prolonged median survival time (59 days versus 40 days) after treatment at 100 mg/kg p.o. 2d on/5d off. It also showed significant anti-tumor activity in a nude mouse model of B-cell lymphoma (Ramos) with a tumor growth inhibition of 63% (15 mg/kg i.p. 5d on/5d off). These results demonstrate the therapeutic potential of this novel kinase inhibitor for the treatment of hematological malignancies.