Comparative biochemical kinase activity analysis identifies rivoceranib as a highly selective VEGFR2 inhibitor

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of tumor angiogenesis, is highly expressed across numerous tumor types and has been an attractive target for anti-cancer therapy. However, clinical application of available VEGFR2 inhibitors has been challenged by limited efficacy and a wide range of side effects, potentially due to inadequate selectivity for VEGFR2. Thus, development of potent VEGFR2 inhibitors with improved selectivity is needed. Rivoceranib is an orally administered tyrosine kinase inhibitor that potently and selectively targets VEGFR2. A comparative understanding of the potency and selectivity of rivoceranib and approved inhibitors of VEGFR2 is valuable to inform rationale for therapy selection in the clinic. Here, we performed biochemical analyses of the kinase activity of VEGFR2 and of a panel of 270 kinases to compare rivoceranib to 10 FDA-approved kinase inhibitors (“reference inhibitors”) with known activity against VEGFR2. Rivoceranib demonstrated potency within the range of the reference inhibitors, with a VEGFR2 kinase inhibition IC50 value of 16 nM. However, analysis of residual kinase activity of the panel of 270 kinases showed that rivoceranib displayed greater selectivity for VEGFR2 compared with the reference inhibitors. Differences in selectivity among compounds within the observed range of potency of VEGFR2 kinase inhibition are clinically relevant, as toxicities associated with available VEGFR2 inhibitors are thought to be partly due to their effects against kinases other than VEGFR2. Together, this comparative biochemical analysis highlights the potential for rivoceranib to address clinical limitations associated with off-target effects of currently available VEGFR2 inhibitors.

Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment

“…Several FGFR and VEGFR inhibitors have been developed and used clinically, with each having a unique kinome inhibition profile 36 . Based on their cell-free biochemical 50% inhibitory concentration (IC 50 ) and kinase inhibitory percentage profiles, we built a panel of RTK inhibitors to probe which pathways, or combination of pathways, are essential for AM tumor cell survival.…”

“…Based on their cell-free biochemical 50% inhibitory concentration (IC50) and kinase inhibitory percentage profiles, we built a panel of RTK inhibitors to probe which pathways, or combination of pathways, are essential for AM tumor cell survival. For this drug panel (Figure 2A) we selected a variety of potent VEGFR inhibitors that include Apatinib (Rivoceranib) as an ultra-narrowspectrum VEGFR2/RET inhibitor 36,37 , Anlotinib as a narrow-spectrum FGFR1/pan-VEGFR inhibitor ( 38,39 and company promotional materials), Lenvatinib as a potent pan-VEGFR and pan-FGFR family inhibitor 20,21 , Cabozantinib as a moderately broad inhibitor with no activity against FGFR ( 40 and FDA pharmacology review application number 208692Orig1s000, 12 Oct 2015), and Sunitinib as a broad kinome inhibitor with no FGFR activity (IC50 reported in FDA pharmacology review application number NDA 21-938 and NDA 21-968, 10 Aug 2005). These inhibitors were evaluated for their ability to reduce acral-like fin melanogenesis in a premalignant mitfa-CRKL MC-GFP zebrafish embryo model described previously 6 (Figure 2B).…”

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

“…Apatinib 19 (Figure 4), also named Rivoceranib, is a small molecule TKI, approved in China for gastric cancer treatment. It was showed to block tumor angiogenesis by inhibiting VEGF signal transduction, particularly, binding VEGFR2 (IC 50 = 16 nM) [116].…”