Identification of a Unique Resorcylic Acid Lactone Derivative That Targets Both Lymphangiogenesis and Angiogenesis

We synthesized 11 novel L-783277
derivatives, in which a structure
rigidifying phenyl ring is incorporated into the 14-membered chiral
resorcylic acid lactone system. The SAR study with these substances
demonstrated that 17 possesses excellent kinase selectivity
against a panel of 335 kinases in contrast to L-783277 and inhibits
VEGFR3, VEGFR2, and FLT3 with single-digit nanomolar IC50 values. Also, we found that 21, a stereoisomer of 17, has excellent potency (IC50 = 9 nM) against
VEGFR3 and selectivity over VEGFR2 and FLT3. 17, a potent
dual VEGFR3 and VEGFR2 inhibitor, effectively suppresses both lymphangiogenesis
and angiogenesis in a 3D-microfluidic tumor lymphangiogenesis assay
and in vivo corneal assay while SAR131675 blocks only lymphangiogenesis.
In addition, 17 blocks the endothelial tube formation
and suppresses proliferation of PHE tumor vascular model. 17 will be a valuable templatefor developing therapeutically active
and selective substances that target both lymphangiogenesis and angiogenesis.