TGFBeta receptor antagonists as anticancer agents

转化生长因子- β是一种多肽，由许多肿瘤组织分泌和激活。它们有助于肿瘤侵袭和转移、诱导血管生成和逃避免疫破坏的能力。出于同样的原因，癌细胞本身通常对tgf - β介导的生长抑制难以耐受。这种特殊的情况提出了一个问题，即阻断肿瘤来源的tgf - β对正常组织（基质细胞、微血管内皮细胞和免疫细胞）的作用是否可能构成一种新的癌症治疗方法。在过去，已经采用了几种不同的策略来抵消tgf - β在癌症和其他疾病中的生物效应。这些方法包括使用TGFbeta中和抗体，TGFbeta结合蛋白（如decorin）和TGFbeta a1反义RNA寡核苷酸。使用每种方法的动物实验和小规模临床研究都证明了TGFbeta失活具有预期的抗肿瘤作用。然而，由于技术上的困难和有限的可用性，这些化合物的大规模测试和进一步的临床开发受到了阻碍。我们现在提出了一种替代策略，通过靶向TGFbeta信号传导的关键分子，即I型TGFbeta受体（TbetaR-I）丝氨酸-苏氨酸激酶来阻断TGFbeta的作用。小分子选择性β - 1拮抗剂可能比上述方法更有效，并且在生产和生物利用度方面不应受到相同的限制。我们在SCIOS， Inc.的合作者已经确定了几种有前途的先导化合物，可以在体外细胞系统和无细胞系统中抑制β - i激酶活性。此外，我们已经开发出在体内测量β - i激酶抑制剂效果的能力，使用专有的高灵敏度抗体，选择性地检测磷酸化的Smad2。我们打算在体外使用多种不同的TGFbeta生物学效应检测铅化合物对正常细胞的影响。最佳的tar - 1拮抗剂将在小鼠体内测试其对可移植肿瘤的抗肿瘤活性，特别关注其对转移、血管生成和抗肿瘤免疫的影响。最后，将对化合物的效价、选择性和生物利用度进行优化，以获得具有良好毒性的类似物，可以进一步开发用于临床应用。

Transforming Growth Factor-betas are polypeptides that are constitutively secreted and activated by many carcinomas. They contribute to the tumor's ability to invade and metastasize, to induce angiogenesis and to escape from immune destruction. By the same token, cancer cells themselves are generally refractory to TGFbeta-mediated growth arrest. This particular set of circumstances raises the question whether blocking the effects of tumor-derived TGFbeta on normal tissue (stromal cells, microvascular endothelial cells and immune cells) might constitute a novel approach to cancer treatment. In the past, several different strategies have been employed to counteract the biological effects of TGFbeta in cancer and other diseases. These have included the use of TGFbeta neutralizing antibodies, of TGFbeta- binding proteins, such as decorin, and of TGFbeta1 antisense RNA oligonucleotides. Animal experiments and small-scale clinical studies using each of these approaches have provided proof of concept that inactivation of TGFbeta has the predicted anti-tumor effect. However, larger scale testing and further clinical development of any of these compounds has been marred by technical difficulties and limited availability. We now propose an alternative strategy to blocking TGFbeta action by targeting the key molecule in TGFbeta signaling, i.e. the type I TGFbeta receptor (TbetaR-I) serine-threonine kinase. Small molecular selective TbetaR-I antagonists are likely to be more effective than the approaches mentioned above, and should not be subject to the same limitations in terms of production and bioavailability. Our collaborators at SCIOS, Inc. have identified several promising lead compounds that inhibit TbetaR-I kinase activity in cell-free as well as in cellular systems in vitro. In addition, we have developed the capability to measure effects of TbetaR-I kinase inhibitors in vivo, using a proprietary highly sensitive antibody that selectively detects phosphorylated Smad2. We intend to examine the effects of lead compounds against normal cells in vitro using a number of different assays for TGFbeta's biological effects. The best TbetaR-I antagonists will then be tested for their antitumor activity against transplantable tumors in mice, with particular attention to their effects on metastasis, angiogenesis and anti-tumor immunity. Finally, optimization of the compounds in terms of potency, selectivity and bioavailability will be carried out to derive analogs with a favorable toxicity profile that can be developed further for clinical use.