Small-molecule STAT3 degraders

信号转导和转录激活因子3(STAT3)在人类癌症和癌症中经常被激活。 STAT3信号的异常激活参与肿瘤的发生、发展、耐药和免疫 逃避。因此，STAT3被认为是一个极具吸引力的癌症治疗靶点。然而， 高度有效和选择性的STAT3小分子抑制剂的发现和开发已证明 出于几个原因，非常具有挑战性。 蛋白水解靶向嵌合体(PROTAC)策略最近获得了巨大的势头，其 承诺通过诱导发现和开发一种完全不同类型的新疗法 有针对性的蛋白质降解。我们假设PROTAC STAT3降解器(以下称为STAT3 降解剂)在抑制STAT3转录活性方面可能比STAT3抑制剂有效得多。 到目前为止，还没有STAT3降解器的报告。 基于一类高效的STAT3抑制剂，我们设计并开发了一流的 STAT3降解剂，如我们的先导化合物SD-36。SD-36是一种高效、高效的 诱导STAT3蛋白的降解，并显示出比其他状态绝对的选择性 成员和所有其他&gt；5000种蛋白质被检查。SD-36对STAT3的降解导致了强健的 肿瘤中STAT3转录活性的抑制和转录网络的下调 细胞。我们的初步筛选显示SD-36抑制AML和ALCL细胞亚群的生长 表达高水平的p-STAT3(Y705)。我们的药效学(PD)研究表明，单个 静脉注射SD-36能够使STAT3蛋白减少90%，且效果持续 三天以上。SD-36在小鼠多种异种移植模型中的肿瘤完全消退 容忍无聊的日程安排。我们的数据表明，STAT3蛋白的降解是一个非常有前途的 癌症治疗策略。 基于我们令人信服的初步数据，我们建议设计、合成和开发高度有效的 小分子STAT3降解剂作为一类治疗人类癌症的新疗法 阐明它们的作用机制。除了在体外和体外对SD-36进行广泛的评估外 在体内，我们将进一步优化SD-36的效力和疗效，并解决我们发现的任何弱点 SD-36。我们的目标是选择一个或多个高效和优化的STAT3降解器用于高级 用激活的STAT3治疗人类癌症的临床前研究进展

Signal transducers and activator of transcription 3 (STAT3) is frequently activated in human cancers and aberrant activation of STAT3 signaling is involved in tumor initiation, progression, drug resistance and immune evasion. Thus, STAT3 has been considered to be a highly attractive cancer therapeutic target. However, discovery and development of highly potent and selective small-molecule inhibitors of STAT3 have proven to be very challenging for a number of reasons. The proteolysis targeting chimera (PROTAC) strategy has recently gained tremendous momentum for its promise for the discovery and development of an entirely different type of new therapeutics through inducing targeted protein degradation. We hypothesize that PROTAC STAT3 degraders (hereafter called STAT3 degraders) may be much more effective than STAT3 inhibitors in inhibition of STAT3 transcriptional activity. To date, no STAT3 degraders have been reported. Based upon a class of highly potent STAT3 inhibitors, we have designed and developed the first-in-class STAT3 degraders, as exemplified by our lead compound SD-36. SD-36 is highly potent and effective in inducing the degradation of STAT3 protein and demonstrates an absolute selectivity over other STAT members and all other >5,000 proteins examined. Degradation of STAT3 by SD-36 results in a robust suppression of STAT3 transcription activity and down-regulation of STAT3 transcription network in tumor cells. Our initial screening demonstrated that SD-36 inhibits the growth of a subset of AML and ALCL cell lines that express high levels of p-STAT3 (Y705). Our pharmacodynamic (PD) studies showed that a single intravenous administration of SD-36 is capable of reducing STAT3 protein by >90%, with the effect persisted for more than 3 days. SD-36 achieves complete tumor regression in multiple xenograft models in mice at well tolerate doss-schedules. Our data demonstrate that degradation of STAT3 protein is a highly promising cancer therapeutic strategy. Based upon our compelling preliminary data, we propose to design, synthesize and develop highly potent small-molecule STAT3 degraders as a new class of therapies for the treatment of human cancer and to elucidate their mechanism of action. In addition to performance of extensive evaluations of SD-36 in vitro and in vivo, we will further optimize SD-36 for potency and efficacy and address any weaknesses we uncover for SD-36. Our goal is to select one or more highly potent and optimized STAT3 degrader for advanced preclinical development for the treatment of human cancers with activated STAT3.