Topic 386: Novel orally bioavailable PDE -catenin inhibitor concentrates in lung for cancer chemoprevention

本申请基于ADT Pharmaceuticals的发现：1）cGMP降解 磷酸二酯酶同工酶，磷酸二酯酶10A（PDE 10），在早期阶段过度表达， PDE 10的基因敲低导致肿瘤细胞的选择性凋亡， cGMP/PKG信号传导;和3）PDE 10的小分子抑制剂通过PKG磷酸化诱导凋亡 致癌β-连环蛋白，从而抑制Tcf介导的编码蛋白质的基因转录， 如存活素，其对于肿瘤细胞存活是必需。从已完成的第一阶段SBIR项目中， 药物化学和筛选活动以及后续化学优化，ADT Pharmaceuticals 开发了一种新的PDE 10抑制剂ADT-030，口服后在肺部浓缩。 ADT-030在多种高侵袭性小鼠中显示出较强的抗肿瘤活性，无明显毒性 肺癌模型，包括癌症化学预防的化学诱导小鼠模型。这里我们 建议进行研究，以评估ADT-030的临床适用口服制剂，我们假设该制剂 是人类肺癌化学预防的理想选择我们预计ADT-030将安全有效地用于肺部 通过在肺部达到高的局部浓度和低的全身水平来预防癌症。

This application is based on ADT Pharmaceuticals' discoveries that: 1) the cGMP degrading phosphodiesterase isozyme, phosphodiesterase 10A (PDE10), is overexpressed during early stages of tumorigenesis; 2) genetic knockdown of PDE10 results in selective apoptosis of tumor cells by activating cGMP/PKG signaling; and 3) small-molecule inhibitors of PDE10 induce apoptosis by PKG phosphorylation of oncogenic β-catenin, thereby suppressing Tcf-mediated transcription of genes that encode for proteins, such as survivin, essential for tumor cell survival. From a completed Phase I SBIR project involving a medicinal chemistry and screening campaign with follow-up chemical optimization, ADT Pharmaceuticals developed a novel PDE10 inhibitor, ADT-030, which concentrates in lungs following oral administration. ADT-030 showed strong antitumor activity without discernable toxicity in multiple highly aggressive mouse models of lung cancer, including a chemical-induced mouse model of cancer chemoprevention. Here we propose studies to evaluate a clinically amenable oral formulation of ADT-030 that we hypothesize will be ideal for lung cancer chemoprevention in humans. We expect ADT-030 will be safe and efficacious for lung cancer chemoprevention by achieving high local concentrations in lungs with low systemic levels.