腺苷-3’,5’-环化-磷酸应答原件结合蛋白（CREB）是一种细胞转录因子，是肿瘤发生、发展及转移的关键因子。抑制CREB可以有效地抑制破骨细胞前体细胞的分化以及乳腺癌细胞的增殖，因此CREB是乳腺癌骨转移瘤的潜在靶标。化合物Naphthol AS-E可以通过抑制KIX-KID相互作用来抑制CREB与CBP的蛋白-蛋白相互作用，从而抑制CREB相关的基因转录。申请人拟在前期工作基础上，一方面以小分子CREB抑制剂Naphthol AS-E为先导化合物，设计、合成新型小分子CREB抑制剂，提高先导化合物的体外CREB抑制活性及其破骨细胞、乳腺癌骨转移瘤细胞抑制活性，并选择高活性化合物进行动物体内药效鉴定，另一方面，我们拟根据已知的KIX-KID结构，建立并优化计算机辅助设计及筛选模型，设计、合成新型结构类型的CREB抑制剂，通过体内外生物活性测试，为CREB抑制剂进一步研究提供苗头化合物。

CREB is a cellular transcription factor which regulates a number of critical genes involved in proliferation, anti-apoptosis and metastasis of cancer cells. CREB inhibitors exhibit good activity in inhibiting osteoclast differentiation and the proliferation of a panel of breast cancer cell lines. Therefore CREB is a potential target for breast cancer bone metastases. The CREB-CBP interaction is mediated by KID in CREB and KIX domain in CBP. Compound Naphthol AS-E was described as a small molecule inhibitor of KIX-KID interaction which mediates CREB-CBP.interaction and CREB-mediated gene transcription. Based on our previous works, Naphthol AS-E will be used as lead compound for optimization and modification to improve biological activity on breast cancer bone metastases models. Furthermore, computer assisted drug design and virtual screening models will be established based on the structure of KIX-KID. Novel CREB inhibitors will be .designed and synthesized which will help the Hit discovery.