CAMBRIDGE, Mass.--(BUSINESS WIRE)--Exo Therapeutics, Inc., a pre-clinical company developing a pipeline of drug candidates that target exosites, unique small-molecule binding pockets that are distinct from traditional active and allosteric sites, to reprogram target enzyme activity for precise and robust therapeutic effects, today presented a late-breaking poster on its preclinical program targeting the TBK1/STING interaction of the cGAS-STING pathway at the American College of Rheumatology’s Convergence Conference (ACR) in Washington, D.C..

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Aberrant activation of the cGAS/TBK1-/STING pathway has been shown to be linked to autoimmune diseases like SLE, CLE, SSc and Sjögren’s. Historically, inhibiting this pathway has proven to be difficult for active-site inhibitors due to their inadequate selectivity, which can lead to off-target effects and narrow therapeutic indices.

cGAS/TBK1-/STING途径的异常激活已被证明与SLE，CLE，SSc和Sjögren等自身免疫性疾病有关。从历史上看，由于活性位点抑制剂的选择性不足，抑制该途径已被证明是困难的，这可能导致脱靶效应和狭窄的治疗指数。

Exo’s approach seeks to overcome these challenges with its novel exosite inhibitors that disrupt STING-mediated TBK1 activation while avoiding the beneficial functions of the kinase on viral suppression and maintenance of autophagy..

Exo的方法试图通过其新型外位点抑制剂来克服这些挑战，该抑制剂破坏STING介导的TBK1激活，同时避免激酶对病毒抑制和维持自噬的有益功能。。

Data presented show that EXO-TBKis, novel TBK1 inhibitors that selectively and potently inhibit the TBK1/STING pathway, demonstrated efficacy in multiple cellular and mouse models as well as patient-derived samples. These findings support the company’s nomination of a lead development candidate for the treatment of autoimmune diseases such as Systemic and Cutaneous Lupus (SLE and CLE), Systemic Sclerosis (scleroderma, SSc) and Sjögren’s Syndrome..

提供的数据表明，EXO-TBKis是一种选择性和有效抑制TBK1/STING途径的新型TBK1抑制剂，在多种细胞和小鼠模型以及患者来源的样品中均显示出功效。这些发现支持该公司提名一名主要开发候选人，用于治疗自身免疫性疾病，如系统性和皮肤狼疮（SLE和CLE），系统性硬化症（硬皮病，SSc）和干燥综合征。。

“Exo’s TBK1 selective exosite inhibitors have demonstrated their ability to potently and selectively inhibit pathogenic effects of TBK1/STING, while sparing beneficial antiviral and cellular functions,” said Dr. Jörg Distler, University of Erlangen. “This approach has the potential to deliver therapeutic benefit to individuals living with autoimmune diseases like SSc and I’m looking forward to the nomination of their lead development candidate based on these promising data.”.

埃尔兰根大学Jörg Distler博士说：“Exo的TBK1选择性外位点抑制剂已经证明它们能够有效和选择性地抑制TBK1/STING的致病作用，同时保留有益的抗病毒和细胞功能。”。“这种方法有可能为患有SSc等自身免疫性疾病的个体提供治疗益处，我期待着根据这些有希望的数据提名他们的主要发展候选人。”。

Data show that an EXO-TBK1i displayed exceptional exosite binding affinity on the target (IC50 -9nM), that translates into double-digit nanomolar potencies in human monocytes, THP1 cells, monocytes and mouse macrophages. EXO-TBK1i were also shown to demonstrate enhanced selectivity when compared to a TBK1 active-site, cGAS and STING inhibitors.

数据显示，EXO-TBK1i在靶标上显示出异常的外位点结合亲和力（IC50-9nM），这在人单核细胞，THP1细胞，单核细胞和小鼠巨噬细胞中转化为两位数的纳摩尔效力。与TBK1活性位点，cGAS和STING抑制剂相比，EXO-TBK1i也显示出增强的选择性。

Additionally, EXO-TBK1is were shown to preserve autophagy, while sparing RIG-I activity with 100-fold selectivity, two activities that are linked to effective immune responses to infection..

此外，EXO-TBK1is被证明可以保留自噬，同时以100倍的选择性保留RIG-I活性，这两种活性与对感染的有效免疫反应有关。。

Dose dependent suppression of p-TBK1, p-STING and inflammatory cytokines were observed in a STING activated DMXAA mouse model. In a disease model, TREX-1 null mouse, EXO-TBK1i was shown to suppress heart inflammation with a dramatic reduction of proinflammatory cytokines including IFNβ, CXCL-10, CXCL-9 and IFIT1.

在STING激活的DMXAA小鼠模型中观察到p-TBK1，p-STING和炎性细胞因子的剂量依赖性抑制。在疾病模型TREX-1无效小鼠中，EXO-TBK1i显示出抑制心脏炎症的作用，并显着降低了促炎细胞因子，包括IFNβ，CXCL-10，CXCL-9和IFIT1。

The TBK1i also displayed dose-dependent inhibition of p-TBK1, p-STING, p-IRF3 and p-P65 in the TREX-1 model..

在TREX-1模型中，TBK1i还显示出对p-TBK1，p-STING，p-IRF3和p-P65的剂量依赖性抑制作用。。

Most notably, EXO-TBK1i demonstrated robust effects in SLE and SSc patient samples. When assessed for activity in SLE patient-derived human whole blood and PBMC, EXO-TBK1i robustly suppressed pathway activation. Similarly, EXO-TBK1i significantly suppressed pathway activation and expression of SMA and stress fibers in SSc patient-derived fibroblasts..

最值得注意的是，EXO-TBK1i在SLE和SSc患者样本中表现出强大的作用。当评估SLE患者来源的人全血和PBMC的活性时，EXO-TBK1i强烈抑制了途径激活。同样，EXO-TBK1i显着抑制了SSc患者来源的成纤维细胞中SMA和应激纤维的途径激活和表达。。

Details of the poster presentations are as follows:

海报展示详情如下：

Abstract Title: Targeted Exosite Inhibition of STING Activation of TBK1 Selectively Blocks Type I Interferon and NFκB Responses for Treatment of Autoimmune Diseases

Presenting Author: Bhavatarini Vangamudi, Ph.D.

演示作者：Bhavatarini Vangamudi博士。

Presentation Type: Poster

展示类型：海报

Session: Late-Breaking Posters (L01 - L14)

课程：迟发海报（L01-L14）

Date: Monday, November 18

日期：11月18日星期一

Presentation Time: 10:30 AM - 12:30 PM

演示时间：上午10:30-下午12:30

Abstract ID: 1943848

摘要编号：1943848

Final Number: L01

最终编号：L01

About Exo Therapeutics

关于Exo Therapeutics

Exo Therapeutics is a small molecule drug discovery and development company co-founded by Professors David R. Liu, Alan Saghatelian and Juan Pablo Maianti with a pioneering technology to address intractable pharmaceutical targets. By leveraging the company’s ExoSightTM platform, Exo is developing a deep pipeline of potent drug candidates that bind exosites, distal and unique binding pockets that have the potential to reprogram enzyme activity for precise and robust therapeutic effect.

Exo Therapeutics是一家小分子药物发现和开发公司，由David R.Liu教授，Alan Saghatelian教授和Juan Pablo Maianti教授共同创立，拥有开创性的技术来解决棘手的药物靶标。通过利用该公司的ExoSightTM平台，Exo正在开发一系列强大的候选药物，这些候选药物可以结合外显子，远端和独特的结合口袋，这些口袋有可能重新编程酶活性以获得精确而强大的治疗效果。

Through this specific and selective approach to challenging targets, the company's team of world-class researchers is unlocking breakthrough therapeutics in inflammation, oncology and a broad range of other diseases. For more information, visit www.exo-therapeutics.com..

通过这种针对具有挑战性目标的具体而有选择性的方法，该公司的世界级研究人员团队正在解锁炎症，肿瘤学和其他广泛疾病的突破性治疗方法。有关更多信息，请访问www.exo-therapeutics.com。。