Multi-target Anti-angiogenesis Small Molecule Prodrug
Abnormal neovascularization, a hallmark of solid tumors, plays a key role in tumor progression. ABT-869 (Linifanib) is an oral multi-target drug, which significantly inhibits angiogenesis-related kinases including VEGFRs, PDGFRs, CSF1R, c-KIT and FLT1/3. Clinical trials of ABT-869 has demonstrated anti-tumor efficacy comparable to similar products, but also high systemic toxicity. To improve its pharmacokinetic characteristics and reduce its systemic toxicity, we have designed a prodrug - 3D011, which is formed by linking ABT-869 and a specific pentapeptide (Asp-Glu4) with a linker (dodecylic acid). 3D011 is stable in vitro, but the linker and the specific pentapeptide could be degraded in vivo by tissue-specific proteases and hydrolases, releasing the active molecule ABT-869 (Linifanib) at the tumor site. Preclinical studies have demonstrated that 3D011 has anti-tumor activity comparable to ABT-869 and less toxicity at the same dose. A series of pre-clinical studies of 3D011, including in vivo and in vitro pharmacokinetic studies, pharmacokinetic/toxicokinetics studies, and safety pharmacology studies have been completed to support clinical trials in patients with advanced tumors.