Screening for Novel CBS Inhibitors for Cancer Therapy

申请人描述(申请人提供)：申请人最近的研究支持内源性气态生物介体硫化氢(硫化氢)在结直肠癌中的作用：选择性上调胱硫醚-b-合酶(CBS)，随后在结肠癌细胞中产生硫化氢，通过刺激肿瘤细胞的生物能量学、生长、增殖、迁移和侵袭，作为促进生存的因素。这项工作确定了CBS是一个新的抗肿瘤靶点。为了推进这一概念的临床翻译，我们将追求以下两个目标：目的1.筛选临床药物、类药物化合物和药理活性分子(&gt；5000化合物)的复合库，以寻找CBS的新型药理抑制剂，目的是将药物重新用于癌症治疗。在AIM#2中，在基于细胞的筛选中确定的抑制剂随后将进入特异性和选择性筛选，随后是生物能量学研究和肿瘤细胞体外增殖研究。目前项目的成功完成将通过确定至少一种临床使用的药物(已用于非肿瘤适应症)来证明，该药物发挥CBS抑制和抗增殖作用，其浓度在治疗上可以达到 病人。这种化合物的成功鉴定将触发第二阶段STTR项目，旨在体内PK/PD研究和临床前IND使能研究，最终导致先导化合物的临床重新用途。申请团队(CBS治疗公司的PI和德克萨斯大学加尔维斯顿分包合同的负责人)拥有进行拟议工作所需的所有必要的理论和实践专业知识。

DESCRIPTION (provided by applicant): Recent studies of the applicants support the role of the endogenous gaseous biological mediator hydrogen sulfide (H2S) in colorectal cancer: selective upregulation of cystathionine-b-synthase (CBS) and the subsequent production of H2S in colonic cancer cells serves as a pro-survival factor by stimulating tumor cell bioenergetics, growth, proliferation, migration and invasion. This work identifies CBS as a novel antitumor target. In order to advance the clinical translation of this concept, we will pursue the following two Aims: Aim #1. To conduct screening a composite library of clinical drugs, drug-like compounds and pharmacologically active molecules (>5,000 compounds) to identify novel pharmacological inhibitors of CBS, with the aim of drug repurposing for cancer therapy. In Aim #2, Inhibitors identified in the cell-based screen will subsequently enter specificity and selectivty screening, followed by bioenergetics studies and studies of tumor cell proliferation in vitro. Successful completion of the current project will be evidenced by the identification of at least one clinically used drug (already used for non-oncological indications), which exerts CBS inhibitory and anti-proliferative effects, at concentrations that are therapeutically achievable in patients. Successful identification of such compound will trigger a Phase II STTR project, aimed at in vivo PK/PD studies and preclinical IND-enabling studies, culminating in the clinical repurposing of the lead compound. The applicant team (the PI at CBS Therapeutics and the head of the subcontract at the University of Texas Galveston) has all necessary theoretical and practical expertise to conduct the proposed work.