Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAFand prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies , NST-628 is positioned to make an impact clinically in an areas of unmet patient need.

中文翻译：

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泛 RAF-MEK 非降解分子胶 NST-628 是 RAS-MAPK 通路的有效脑渗透抑制剂，对多种 RAS 和 RAF 驱动的癌症具有活性

RAS-MAPK 信号级联的改变在多种实体瘤类型中很常见，并且是许多癌症的驱动因素。 NST-628 是一种有效的泛 RAF-MEK 分子胶，可防止 RAF 对 MEK 的磷酸化和激活，克服传统 RAS-MAPK 抑制剂的局限性，并导致该通路的深度持久抑制。 RAF-MEK 复合物的细胞、生化和结构分析表明，NST-628 与 RAF 的所有亚型结合，并阻止 BRAF-CRAF 异二聚体的形成，这是与所有当前 RAF 抑制剂不同的机制。 NST-628 具有对 RAF-MEK 信号复合物有效且持久的抑制作用以及对大脑的高内在渗透性，在具有多种 MAPK 通路改变的细胞和患者来源的肿瘤模型（包括原位颅内模型）中表现出广泛的功效。鉴于其功能和药代动力学机制不同于以往的疗法，NST-628有望在未满足患者需求的领域产生临床影响。