Rebastinib is a clinical stage inhibitor of BCR-ABL and TIE2 kinases, designed using Deciphera Pharmaceuticals' switch pocket technology [Cancer Cell (2011) 19: 556]. Preclinical and clinical data summarizing its utility in the treatment of refractory chronic myeloid leukemia will be presented.  In addition to inhibition of BCR-ABL, rebastinib is 50-times more potent at inhibition of TIE2 kinase, increasingly implicated in stromal mechanisms of cancer drug resistance.  Clinical treatment of solid tumors by radiation or chemotherapy often leads to initial clinical response, followed by resistance and disease progression caused by recruitment of bone marrow derived TIE2-expressing monocytes (TEMs) that re-establish tumor vasculature and invasiveness.  Rebastinib potently blocks this mechanism.  DCC-2701, an inhibitor of TIE2, VEGFR2, and MET kinases, is also being developed to target therapy-induced resistance by blocking major stromal pathways.  Preclinical data will be presented for both rebastinib and DCC-2701, along with summary Phase 1 clinical data on rebastinib.

Rebastinib and DCC-2701: Targeting of resistance mechanisms in cancer treatment

245th National Meeting (2013)

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