Haviv Fortuna, Bradley Michael F, Kalvin Douglas M, Schneider Andrew J, Davidson Donald J, Majest Sandra M, McKay Laura M, Haskell Catherine J, Bell Randy L, Nguyen Bach, Marsh Kennan C, Surber Bruce W, Uchic John T, Ferrero James, Wang Yi-Chun, Leal Juan, Record Rae D, Hodde Jason, Badylak Stephen F, Lesniewski Richard R, Henkin Jack
Global Pharmaceutical Research and Development Organization of Abbott Laboratories, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
J Med Chem. 2005 Apr 21;48(8):2838-46. doi: 10.1021/jm0401560.
The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 microM, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies.
七肽1，NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt，是源自血小板反应蛋白-1（TSP-1）第二个1型重复序列的结构修饰片段，已知具有抗血管生成活性。然而，由于该肽在啮齿动物体内半衰期很短，无法证明其治疗效用。为了优化1的药代动力学/药效学特征，我们启动了一项系统的构效关系研究。最初的结构修饰在肽1的第5和第7位以及N端和C端进行。在合成的数百种肽中，九肽5（ABT-526）成为一个有前景的先导化合物。ABT-526在纳摩尔范围内抑制VEGF诱导的人微血管内皮细胞（HMVEC）迁移和管腔形成，并增加人脐静脉内皮细胞（HUAEC）的凋亡。ABT-526在啮齿动物、犬和猴体内显示出可接受的药代动力学特征。当以10微摩尔浓度掺入植入大鼠角膜的血管生成微丸中时，ABT-526使新血管形成减少了92%。用DalloIle取代ABT-526中的DIle得到九肽6（ABT-510），其在EC迁移中的活性比ABT-526低30倍，但在管腔形成试验中活性高20倍。与ABT-526相比，ABT-510在犬和猴体内的水溶性增加且清除较慢。放射性标记的ABT-510在0.02 - 20纳摩尔浓度下显示出与HMVEC细胞的饱和结合，并且可被TSP-1取代。ABT-510和ABT-526均显示能显著增加HUAEC细胞的凋亡。ABT-510在小鼠基质胶栓模型中有效阻断新血管形成，并在小鼠Lewis肺癌模型中抑制肿瘤生长。先前的研究表明，ABT-510在同基因小鼠中有效抑制鼠黑色素瘤转移灶的生长，并在裸鼠中阻断人膀胱癌的生长。还表明ABT-510可使宠物狗的肿瘤病灶消退或在晚期犬癌中使疾病意外稳定。ABT-526和ABT-510是模拟TSP-1抗血管生成功能的强效血管生成抑制剂类中的首批化合物。ABT-510目前正处于II期临床研究阶段。
