Activity of ARRY-614, an Inhibitor of p38 Map Kinase and Angiogenic Targets, in Hematologic Malignancies.

Multiple Myeloma (MM) is a malignancy characterized by the clonal expansion of plasma cells within the bone marrow microenvironment. Within this compartment, the proliferative capacity of MM cells is enhanced by pro-inflammatory cytokines, and there is growing recognition that bone marrow stromal cells play an important role in the support of MM growth and chemo-resistance. We have identified a series of compounds, of which ARRY-614 is representative, that are potent inhibitors (EC50<10 nM) of cytokine synthesis through the inhibition of p38 MAPK. This compound is also a potent inhibitor of Abl tyrosine kinases and Tie2/Tek receptor tyrosine kinase. ARRY-614 is active against all of these targets on both the isolated enzymes and in cells. To confirm these activities, ARRY-614 was evaluated in relevant in vitro and in vivo models. ARRY-614 inhibited p38α in ex vivo stimulated human whole blood (EC50=2 nM) and the release of IL-6 and TNFα from SEA- or LPS-challenged mice (ED50<10 mg/kg). Further, ARRY-614 administered as a single agent was efficacious at inhibiting bFGF-driven angiogenesis in an in vivo matrigel invasion assay as well as inhibiting tumor growth in subcutaneous K562 (BCR-Abl dependent) and RPMI 8226 (multiple myeloma) tumor xenografts in mice, at doses ranging from 30 to 100 mg/kg qd, PO. In regulated safety studies, this compound was well-tolerated at doses up to 100 mg/kg qd and 30 mg/kg qd in rats and cynomolgus, respectively. Together, these data support the advancement of this agent into clinical trials for hematologic malignancies.