Multitargeted kinase inhibition and sustained biological effects of CHIR-258 contribute to enhanced preclinical efficacy

678 Cancer is a complex disease that involves multiple genetic defects that drive tumor-cell proliferation, suggesting that simultaneously inhibiting multiple cell signaling pathways may lead to a more favorable therapeutic outcome. In this work we examined the activity of CHIR-258, a novel, orally active, small molecule, that exhibits a multitarget kinase selectivity against Class III, IV and V receptor tyrosine kinases (RTKs). Biochemical IC50s of CHIR-258 for FLT3 = 1 nM; cKIT = 2 nM; VEGFR1/2/3 ∼ 8 nM; FGFR1/3 ∼ 10nM;, PDGFRb = 27 nM; and CSF-R1 = 36 nM. The in vivo activity of CHIR-258 was shown to result from direct inhibition of RTK signaling and consequent induction of apoptosis in tumor cells, in addition to potent inhibition of angiogenesis. The anti-tumor efficacy of CHIR-258 was evaluated in a variety of murine and human solid tumor models (colon, prostate, breast, ovarian) and hematological cancers (leukemia and myeloma), and compared with that of more “selective” kinase inhibitors currently in clinical development. In solid tumor models, CHIR-258 exhibited potent tumor inhibition, including regression, and was more effective than more “selective” RTK inhibitors. When compared to a RTK inhibitor with a similar target profile and “broad” selectivity as CHIR-258, efficacy was generally equivalent with continuous daily dosing. However, CHIR-258 exhibited more potent anti-tumor activity when cyclic or intermittent dosing schedules were evaluated. Pharmacodynamic studies have shown that target modulation and inhibition of signaling pathways were maintained for 24 hours followed by induction of tumor cell apoptosis. Our data suggests that biological activity of CHIR-258 is dependent upon degree and duration of response, which likely plays a role in the efficacy observed in the absence of continuous drug treatment and differentiates CHIR-258 from other RTK inhibitors. In conclusion, these data support the development of multitargeted agents like CHIR-258 based on our understanding of the relative contributions of the disease-relevant targets in tumorigenesis.