Developing small-molecule probes for protein arginine methyltransferases

 描述（由申请人提供）：我们研究计划的长期目标是建立一个靶向蛋白质精氨酸甲基转移酶（PRMT）的平台，开发小分子探针，以研究PRMT作为可行的治疗靶点，并提供先导化合物，以开发基于PRMT的癌症新诊断和治疗。该提案的目的是验证用于开发各种PRMT抑制剂的一般基于结构的方法，并鉴定CARM1的选择性小分子抑制剂，以研究CARM1在癌症中的化学抑制的治疗潜力。所提出的方法建立在我们在合成化学，检测开发以及分子和细胞生物学方面的现有专业知识基础上，并利用我们与癌症生物学，计算和蛋白质组学专家的密切合作。该提议的中心假设是小分子可以通过干扰单个PRMT与辅因子SAM甲基供体或精氨酸底物的选择性结合来调节特定PRMT的功能。为了实现本申请的目的，将追求以下两个具体目标。目的1）构建一系列具有PRMT化学抑制作用的SAM模拟物和精氨酸模拟物。目的2）鉴定CARM1抑制剂并验证化学抑制CARM1在癌症中的治疗潜力。通过这项探索性资助，新的CARM1小分子抑制剂的鉴定将验证所提出的基于结构的方法的普遍适用性，用于开发具有前景的癌症治疗靶点的各种PRMT抑制剂。此外，鉴定的CARM1小分子抑制剂将首次提供细胞活性先导化合物，用于发现新的诊断生物标志物和治疗CARM1相关的乳腺癌和前列腺癌。

 DESCRIPTION (provided by applicant): The long-term goal of our research program is to establish a platform targeting protein arginine methyltransferases (PRMTs) that develops small-molecule probes to investigate PRMTs as viable therapeutic targets and to provide lead compounds toward developing PRMT-based new diagnosis and treatment in cancers. The objective of this proposal is to validate a general structure-based approach for developing inhibitors of various PRMTs and to identify selective small-molecule inhibitors of CARM1 for investigating therapeutic potentials of chemical inhibition of CARM1 in cancer. The proposed approach builds upon our existing expertise in synthetic chemistry, assay development, and molecular and cell biology, and leverages our strong collaboration with experts in cancer biology, computation and proteomics. The central hypothesis of this proposal is that small molecules could modulate the function of specific PRMTs by interfering the selective binding of individual PRMT with co-factor SAM methyl donor or arginine substrate. To accomplish the objective of this application the following two specific aims will be pursued. Aim 1) Construct a collection of SAM-mimic and arginine mimic compounds targeting chemical inhibition of PRMTs. Aim 2) Identify CARM1 inhibitors and validate therapeutic potentials of chemical inhibition of CARM1 in cancers. Through this exploratory grant, the identification of novel small-molecule inhibitors of CARM1 will validate the general applicability of the proposed structure-based approach for developing inhibitors for various PRMTs of promising cancer-therapeutic targets. Furthermore, the identified small-molecule inhibitors of CARM1 will, for the first time, provide cell-active lead compounds for the discovery of new diagnostic biomarkers and therapeutic treatment for CARM1-assoscaited breast and prostate cancers.