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

本申请基于ADT制药公司的发现：1)cGMP降解 磷酸二酯酶同工酶，磷酸二酯酶10A(PDE10)，在早期阶段过表达。 肿瘤的发生；2)PDE10的基因敲除通过激活导致肿瘤细胞的选择性凋亡 CGMP/PKG信号转导；3)PDE10小分子抑制剂通过PKG磷酸化诱导细胞凋亡 致癌的β-连环蛋白，从而抑制Tcf介导的编码蛋白质的基因的转录， 如Survivin，对肿瘤细胞的生存至关重要。来自已完成的第一阶段SBIR项目，涉及 药物化学和筛选活动与后续化学优化，ADT制药 开发了一种新型的PDE10抑制剂ADT-030，口服后集中在肺部。 ADT-030在多种高侵袭性小鼠体内显示出较强的抗肿瘤活性，且无明显毒性 肺癌模型，包括化学诱导的癌症化学预防小鼠模型。在这里我们 建议进行研究以评估ADT-030的临床顺应性口服制剂，我们假设该制剂将是 是人类肺癌化学预防的理想选择。我们预计ADT-030对肺部是安全有效的。 通过在肺部实现较高的局部浓度和较低的全身水平来化学预防癌症。

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.