BOSTON--(BUSINESS WIRE)--Nimbus Therapeutics, LLC ('Nimbus Therapeutics' or 'Nimbus'), a biotechnology company that designs and develops breakthrough medicines for patients through its powerful computational drug discovery engine, announced that it is presenting preclinical data on its new development candidate, NTX-452, a novel Werner syndrome helicase (WRN) inhibitor, at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, taking place October 23-25, 2024 in Barcelona, Spain..

波士顿--（商业新闻短讯）--Nimbus Therapeutics，LLC（“Nimbus Therapeutics”或“Nimbus”）是一家通过强大的计算药物发现引擎为患者设计和开发突破性药物的生物技术公司，宣布将在2024年10月23日至25日于西班牙巴塞罗那举行的第36届EORTC-NCI-AACR分子靶标和癌症治疗研讨会上提供其新开发候选者NTX-452（一种新型Werner综合征解旋酶（WRN）抑制剂）的临床前数据。。

WRN is a helicase required for DNA replication and DNA repair and is a validated target for tumors with microsatellite instability (MSI). MSI is a phenotypic consequence of defective mismatch repair (dMMR) and occurs in various tumor types, including colorectal, gastric and endometrial cancers. Inhibition of WRN activity has the potential to induce synthetic lethality in MSI-high (MSI-H) tumors.

WRN是DNA复制和DNA修复所需的解旋酶，是微卫星不稳定性（MSI）肿瘤的有效靶标。MSI是错配修复缺陷（dMMR）的表型结果，发生在各种肿瘤类型中，包括结直肠癌，胃癌和子宫内膜癌。WRN活性的抑制有可能在MSI高（MSI-H）肿瘤中诱导合成致死率。

Using a structure-based drug design approach, Nimbus developed highly potent and selective covalent and non-covalent inhibitors of WRN, and has selected a novel non-covalent inhibitor, NTX-452, as the clinical candidate..

使用基于结构的药物设计方法，Nimbus开发了高效和选择性的WRN共价和非共价抑制剂，并选择了一种新型非共价抑制剂NTX-452作为临床候选药物。。

In a poster (abstract #356) titled 'Preclinical Characterization of NTX-452, a Potent, Selective and Highly Efficacious WRN Inhibitor for the Treatment of MSI-H Tumors,' Nimbus is presenting new data from preclinical assays and several tumor models that support the potential of the company’s non-covalent WRN inhibitor as a treatment for MSI-H tumors..

在一张题为“NTX-452（一种用于治疗MSI-H肿瘤的有效，选择性和高效的WRN抑制剂）的临床前表征”的海报（摘要#356）中，Nimbus提供了来自临床前测定和几种肿瘤模型的新数据，这些数据支持该公司的非共价WRN抑制剂作为MSI-H肿瘤治疗的潜力。。

Key findings from the preclinical studies include:

临床前研究的主要发现包括：

NTX-452 demonstrated potent and selective inhibition of WRN activity with favorable drug-like properties.

NTX-452表现出对WRN活性的有效和选择性抑制，具有良好的药物样特性。

The compound showed synthetic lethality in MSI-H tumor cells, triggering a DNA damage response that suppressed cell viability and promoted cell death.

该化合物在MSI-H肿瘤细胞中显示出合成致死性，引发DNA损伤反应，抑制细胞活力并促进细胞死亡。

Treatment with NTX-452 at low doses in vivo exhibited a robust pharmacodynamic response, resulting in tumor regression across multiple MSI-H cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) tumor models, including established models for colorectal, gastric and endometrial cancers..

体内低剂量NTX-452治疗表现出强大的药效学反应，导致多种MSI-H细胞系衍生的异种移植物（CDX）和患者衍生的异种移植物（PDX）肿瘤模型的肿瘤消退，包括已建立的结直肠癌，胃癌和子宫内膜癌模型。。

Significant tumor regression and complete responses were observed at low oral doses in MSI-H models refractory to immunotherapy and chemotherapy.

在免疫治疗和化疗难治的MSI-H模型中，低剂量口服后观察到明显的肿瘤消退和完全缓解。

'These compelling preclinical results for NTX-452 further highlight the significant potential of our WRN inhibitor as a promising therapeutic approach for patients with MSI-H tumors, many of whom fail to respond to or eventually relapse with current standard of care therapies including immune checkpoint inhibitors,' said Peter Tummino, Ph.D., Chief Scientific Officer of Nimbus.

Nimbus首席科学官彼得·图米诺（PeterTummino）博士说：“NTX-452的这些令人信服的临床前结果进一步突显了我们的WRN抑制剂作为MSI-H肿瘤患者的一种有前途的治疗方法的巨大潜力，其中许多患者对包括免疫检查点抑制剂在内的当前标准治疗方法无效或最终复发。”。

'Our novel non-covalent approach to WRN inhibition, coupled with the robust efficacy demonstrated across diverse tumor types and treatment settings, positions our program for potential best-in-class status. We are particularly encouraged by the low doses required to achieve robust anti-tumor activity in preclinical models, which may translate to an improved benefit-risk profile in the clinic.'.

“我们新颖的非共价WRN抑制方法，加上在不同肿瘤类型和治疗环境中表现出的强大功效，使我们的计划处于潜在的同类最佳状态。我们特别受到鼓舞的是，在临床前模型中实现强大的抗肿瘤活性所需的低剂量，这可能会改善临床中的利益风险状况。”。

The preclinical profile of NTX-452 suggests several potential advantages in the treatment of MSI-H tumors, including:

The non-covalent mechanism may offer more durable on-target activity, and a greater safety window compared to covalent inhibitors.

。

High potency and favorable pharmacokinetic properties indicate the potential for target levels of efficacy at lower doses.

高效力和有利的药代动力学特性表明在较低剂量下可能达到目标疗效水平。

Broad efficacy across treatment-naïve, chemotherapy-pretreated, and immunotherapy-pretreated models suggests potential utility in both early-stage and advanced disease settings.

未经治疗，化疗预处理和免疫治疗预处理模型的广泛疗效表明，在早期和晚期疾病环境中都具有潜在的实用性。

Activity in multiple MSI-H tumor types, including those with diverse genetic alterations, indicates potential broad applicability across dMMR/MSI-H cancers.

在多种MSI-H肿瘤类型（包括具有多种遗传改变的肿瘤）中的活性表明，dMMR/MSI-H癌症具有潜在的广泛适用性。

Nimbus is advancing NTX-452 with plans to enter the clinic in the first half of 2025.

。

About Nimbus Therapeutics

关于Nimbus Therapeutics

Nimbus Therapeutics is a clinical-stage, structure-based drug discovery company developing novel small molecule medicines designed to act against well-validated but difficult-to-drug targets implicated in multiple human diseases. The company advances promising research based on a unique strategy that combines leading-edge computational technologies with a tailored array of machine learning-based predictive modeling approaches.

Nimbus Therapeutics是一家临床阶段，基于结构的药物发现公司，开发新型小分子药物，旨在对抗多种人类疾病中经过充分验证但难以药物靶点。该公司基于独特的策略推进了有前景的研究，该策略将前沿计算技术与定制的基于机器学习的预测建模方法相结合。

Nimbus' pipeline includes a clinical-stage HPK1 inhibitor for the treatment of cancer (NCT05128487), as well as a diverse portfolio of preclinical programs focused on cancer, including the WRN program, autoimmune conditions, and metabolic diseases. The company is headquartered in Boston, Mass. To learn more about Nimbus, please visit www.nimbustx.com..

Nimbus的管道包括用于治疗癌症的临床阶段HPK1抑制剂（NCT05128487），以及针对癌症的多种临床前计划，包括WRN计划，自身免疫疾病和代谢疾病。该公司总部位于马萨诸塞州波士顿。有关Nimbus的更多信息，请访问www.nimbustx.com。。