2-Cyanopyridines As Novel Vegfr-2 / Vegfr-3 Inhibitors. Part 2. Inhibition Of Tumor Growth And Metastasis By A Cyanopyridine

Proc Amer Assoc Cancer Res, Volume 47, 2006 3769 Therapies aimed at inhibiting tumor angiogenesis and lymphangiogenesis are expected to deprive malignant tissues of their oxygen and nutrient supplies, and to also prevent tumors from eliminating metabolic wastes. This, in turn, would inhibit the tumor growth and metastatic progression that accompanies most advanced cancers. High throughput screening followed by lead optimization led to the development of a diaryl urea containing a distal 2-cyanopyridine as the program lead. This lead compound possesses potent activity against both VEGFR3 and VEGFR2 but no activity against c-ErbB1/2, FLT3, FGFR1, LCK and many other kinases. Several in vivo studies were carried out to determine the effect of the lead compound on tumor growth and metastasis. In an MDA-MB-231 breast tumor model, the cyanopyridine inhibited tumor growth by 85% when dosed once a day for 9 days at 10 mg/kg (mpk). In a separate study using the MDA-MB-231 model, dosing was stopped after 9 days and tumor growth was monitored for 55 days. A growth delay of 36 days was observed, along with 4 of 10 tumors achieving complete regression and 5 of 10 achieving partial regression. Moreover, several intermittent dosing-schedules were tested in the MDA-MB-231 model. When dosed orally at 30 mpk every other day (Q2Dx5), every third day (Q3Dx4) or every fourth day (Q4Dx3), the cyanopyridine inhibited tumor growth by 96%, 82% and 73%, respectively. The lead compound proved active in a variety of models of tumor growth. When dosed at 30 mpk, the cyanopyridine inhibited tumor growth by 78% in a LOX melanoma model, by 86% in a 22RV-1 prostate model, and by 78% in a Colo205 colon model. In an HCT-15 colon model (MDR) and an H460 NSCLC model, the lead compound inhibited tumor growth by 67% and 42%, respectively, when dosed daily at 10 mpk. CD-31 and α-smooth muscle actin levels in tumors from the MDA-MB-231 model were analyzed by immunohistochemistry, showing a strong decrease in tumor angiogenesis. Furthermore, the effect of the compound on cancer cell metastasis was assessed in an MDA-MB-435 orthotopic model. Eight weeks after tumor implantation in the fat pad, the compound was dosed daily for 21 days. Lung examination by histology (H&E) revealed numerous foci in lungs of control groups, but no foci were observed in lungs of the compound-treated group. Similar results were obtained in a LOX melanoma model in which real-time PCR was used to detect lung and lymph node micro-metastases. Overall, these results show the ability of the lead compound to inhibit tumor growth and metastasis in multiple subcutaneous and orthotopic tumor models.