Development of small molecule inhibitors as anti-inflammatory agents and antidotes for arsenicals

砷会引起皮肤迅速、严重和疼痛的炎症和起泡反应。可用 针对砷诱导的毒性的医学对策由于毒性和低治疗性而无效， 指数.因此，需要开发更有效和毒性更小的砷解毒剂。 开发含溴结构域蛋白4（BRD 4）的杂合抑制剂，其负责 调节炎症基因，受体相互作用蛋白激酶-3（RIP 3，或RIPK 3），一个中心球员， 白细胞介素-6（IL-6）可能是一种有效的治疗方法， 炎症我们已经鉴定了三种有效的BRD 4、RIPK 3抑制剂SRI-43887、SRI-47362和SRI-47561， 和IL 6。例如，SRI-43887在体内表现出显著的抗氧化苯胂（PAO）和 砷（路易氏剂）诱导的小鼠。这些化合物的持续优化将导致识别 治疗砷剂相关皮肤损伤的潜在临床前候选药物。实现 为了实现这一目标，我们将（i）利用分子模拟来设计和合成这三种先导化合物的类似物 并在体外测试BRD 4、RIPK 3和IL 6抑制活性;（ii）评估所选化合物的细胞毒性， 体外药物样性质（溶解度、代谢稳定性、log D、渗透性）;（iii）测定体内药物样性质; 药代动力学特征（生物利用度和半衰期）;和（iv）对选择的化合物进行体内研究， PAO和路易氏剂来确定这些化合物的功效。这些目标将通过一个 团队在药物设计，药物化学， 计算化学、生物测定、药代动力学、分子生物学和药物开发。

Arsenicals cause rapid, severe and painful inflammatory and blistering responses in the skin. The available medical countermeasures against arsenical-induced toxicity are not effective due to toxicity and a low therapeutic index. Hence, there is a demand for the development of more effective and less toxic antidotes for arsenicals. Developing hybrid inhibitors of bromodomain-containing protein 4 (BRD4) which are responsible for the regulation of inflammatory genes, receptor-interacting protein kinase-3 (RIP3, or RIPK3), a central player in necroptosis, and interleukin-6 (IL-6) would be an effective and efficient treatment to attenuate arsenical-induced inflammation. We have identified three potent inhibitors, SRI-43887, SRI-47362 and SRI-47561 of BRD4, RIPK3 and IL6. For example, SRI-43887 exhibited significant activity in vivo against phenylarsine oxide (PAO) and arsenicals (Lewisite)-induced mice. Continued optimization of these compounds will lead to the identification of a potential preclinical candidate(s) for the treatment of cutaneous injuries associated with arsenicals. To achieve this goal, we will (i) utilize molecular modeling to design and synthesize analogs of these three lead compounds and test in vitro for BRD4, RIPK3 and IL6 inhibitory activity; (ii) evaluate select compounds for cytotoxicity and in vitro drug-like properties (solubility, metabolic stability, log D, permeability); (iii) determine the in vivo pharmacokinetic profile (bioavailability and half-life); and (iv) perform in vivo studies on select compounds against PAO and Lewisite to determine the efficacy of these compounds. These goals will be accomplished through a collaborative effort involving a team with extensive experience in drug design, medicinal chemistry, computational chemistry, biological assays, pharmacokinetics, molecular biology and drug development.