TGFBeta receptor antagonists as anticancer agents

TGFβ受体拮抗剂作为抗癌剂

基本信息

批准号：
6515267
负责人：
Michael Reiss
金额：
$ 24.36万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2005-06-30
项目状态：
已结题

项目摘要

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.

转化生长因子-Betas是多肽，由许多癌构成分泌和激活。它们有助于肿瘤侵袭和转移，诱导血管生成并摆脱免疫破坏的能力。同样，癌细胞本身通常对TGFBETA介导的生长停滞难治。这种特殊的情况提出了一个问题，是否阻止了肿瘤衍生的TGFBETA对正常组织（基质细胞，微血管内皮细胞和免疫细胞）的影响可能构成一种新型的癌症治疗方法。过去，已经采用了几种不同的策略来抵消TGFBETA在癌症和其他疾病中的生物学作用。其中包括使用TGFBETA中和抗体的使用，TGFBETA结合蛋白（例如DecorIn和TGFBETA1反义RNA RNA寡核苷酸）的使用。动物实验和小规模的临床研究使用每种方法都提供了概念证明，表明TGFBETA失活具有预测的抗肿瘤作用。但是，任何这些化合物中的任何一种大规模测试和进一步的临床开发都受到技术困难和有限的可用性的破坏。现在，我们提出了一种替代策略来通过靶向TGFBETA信号传导中的关键分子，即I型TGFBETA受体（TBETAR-I）丝氨酸丝氨酸 - 硫代激酶来阻止TGFBETA作用。小分子选择性TBETAR-I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希望的铅化合物，这些化合物在体外抑制了无细胞和细胞系统中的TBETAR-I激酶活性。此外，我们还开发了使用专有的高敏感抗体在体内测量TBETAR-I激酶抑制剂的作用的能力，该抗体有选择地检测到磷酸化的SMAD2。我们打算使用许多不同的TGFBETA生物学作用来检查铅化合物对正常细胞的影响。然后，最好的TBETAR-I拮抗剂将测试其针对小鼠的可移植肿瘤的抗肿瘤活性，并特别注意它们对转移，血管生成和抗肿瘤免疫的影响。最后，将在效力，选择性和生物利用度方面优化化合物，以得出具有良好毒性特征的类似物，可以进一步开发供临床使用。