Kit inhibitor APcK110 extends survival in an AML xenograft mouse model.

BACKGROUND: Constitutive activation of kit contributes to pathogenesis of acute myeloid leukemia (AML) and targeting Kit may be of therapeutic benefit. APcK110, a novel inhibitor of Kit, has potent proapoptotic and antiproliferative activity in AML cell lines and primary AML samples. Here we extend our studies to the activity of APcK110 in a xenograft mouse model. METHODS: After sub-lethal whole body radiation, OCI/AML3 cells were injected intravenously in NOD-SCID mice. Ten days later, either APcK110 or phosphate buffered saline (PBS) was injected intraperitoneally every other day. Kaplan-Meier estimates were used to calculate survival. RESULTS: We show that 1) all mice injected with OCI/AML3 cells developed a clinical and histological picture consistent with myelomonocytic AML; and 2) survival of APcK110-treated mice was significantly longer compared with mice injected with PBS (p = .02). CONCLUSIONS: APcK110 is a novel kit kinase inhibitor with anti-AML activity in vitro and in vivo. Further evaluation in toxicology and clinical studies is warranted.

Studies toward the total synthesis of ristocetin A aglycone using arene-ruthenium complexes as S(N)Ar substrates: Construction of an advanced tricyclic intermediate.

Ruthenium-mediated S(N)Ar reactions are used to construct the diaryl ether linkages in two key intermediates for a projected total synthesis of the aglycone of ristocetin A.

Synthesis of a key precursor for orienticin C and model study on ruthenium-mediated macrocyclization.

A tripeptido--arene--ruthenium complex was prepared as a key precursor for the projected synthesis of orienticin C, demonstrating that the cyclopentadienylruthenium moiety can be attached to a chloroarene in the presence of multiple functionality. The ruthenium-mediated intramolecular SNAr reaction for formation of the required diaryl ether linkage was successfully tested on a model system.