Small-molecule STAT3 degraders

信号转导子和转录激活子3（STAT 3）在人类癌症中经常被激活， STAT 3信号传导的异常激活参与肿瘤的发生、发展、耐药性和免疫应答。 逃避因此，STAT 3被认为是一个非常有吸引力的癌症治疗靶点。然而，在这方面， 已经证明，STAT 3的高效和选择性小分子抑制剂的发现和开发， 因为很多原因，这是非常具有挑战性的。 蛋白质水解靶向嵌合体（PROTAC）策略最近获得了巨大的动力，因为它 通过诱导，有希望发现和开发一种完全不同类型的新疗法， 靶向蛋白质降解。我们假设PROTAC STAT 3降解剂（以下称为STAT 3 降解物）在抑制STAT 3转录活性方面可能比STAT 3抑制剂有效得多。 到目前为止，还没有STAT 3降解剂的报道。 基于一类高效的STAT 3抑制剂，我们设计并开发了一流的 STAT 3降解剂，如我们的先导化合物SD-36所示。SD-36是非常有效的， 诱导STAT 3蛋白的降解，并显示出相对于其他STAT的绝对选择性 成员和所有其他> 5，000蛋白质检查。SD-36对STAT 3的降解产生了稳健的 肿瘤中STAT 3转录活性抑制和STAT 3转录网络下调 细胞我们的初步筛选表明，SD-36抑制AML和ALCL细胞系亚群的生长 表达高水平的p-STAT 3（Y 705）。我们的药效学（PD）研究表明， SD-36的静脉内给药能够使STAT 3蛋白减少> 90%，并且效果持续 超过3天。SD-36在小鼠多个异种移植模型中达到完全肿瘤消退， 容忍剂量表。我们的数据表明，STAT 3蛋白的降解是一种非常有前途的方法， 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，合成和开发高效的 小分子STAT 3降解剂作为一类新的治疗人类癌症的疗法， 阐明其作用机制。除了在体外对SD-36进行广泛评价外， 在体内，我们将进一步优化SD-36的效力和功效，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STAT 3降解剂，用于高级 用于用活化的STAT 3治疗人类癌症的临床前开发。

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.