NVL-655 是多种 ALK 突变癌蛋白（包括 Lorlatinib 耐药化合物突变）的选择性脑渗透抑制剂。
NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations.
发表日期：2024 Sep 13
作者：
Jessica J Lin, Joshua C Horan, Anupong Tangpeerachaikul, Aurélie Swalduz, Augusto Valdivia, Melissa L Johnson, Benjamin Besse, D Ross Camidge, Toshio Fujino, Satoshi Yoda, Linh Nguyen-Phuong, Hayato Mizuta, Ludovic Bigot, Catline Nobre, Jii Bum Lee, Mi Ra Yu, Scot Mente, Yuting Sun, Nancy E Kohl, James R Porter, Matthew D Shair, Viola W Zhu, Enriqueta Felip, Byoung Chul Cho, Luc Friboulet, Aaron N Hata, Henry E Pelish, Alexander Drilon
来源：
Cancer Discovery
摘要：
三代酪氨酸激酶抑制剂（TKI）已被批准用于治疗间变性淋巴瘤激酶（ALK）融合阳性非小细胞肺癌。然而，没有一个能够解决广泛的耐药覆盖、大脑活动和避免临床剂量限制性 TRK 抑制的综合需求。 NVL-655 是一种合理设计的 TKI，对 96% 的测试激酶组中的 ALK 选择性超过 50 倍。在体外，NVL-655 抑制多种 ALK 融合、激活改变和耐药突变，与已批准的 ALK TKI 相比，针对 ALKG1202R 单一和复合突变的效力提高了 100 倍以上。在体内，它可诱导 12 种肿瘤模型的消退，包括颅内和患者来源的异种移植物。 NVL-655 抑制 ALK 的选择性高于 TRK 的 22 倍至 >874 倍。这些临床前研究结果得到了正在进行的 NVL-655 首次人体 I/II 期试验的三个案例研究的支持，该试验证明了在经过大量预处理的 ALK 融合阳性非小细胞肺患者中的初步概念验证临床活性癌症，包括患有脑转移和单一或复合 ALK 耐药突变的患者。意义：通过结合针对单一和复合 ALK 耐药突变的广泛活性、脑外显率和选择性，NVL-655 解决了目前批准的 ALK 抑制剂的关键局限性，并有可能代表作为 ALK 患者的第四代抑制剂的明显进步-驱动的癌症。©2024 作者；由美国癌症研究协会出版。
Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion-positive non-small cell lung cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity for ALK over 96% of the kinome tested. In vitro, NVL-655 inhibits diverse ALK fusions, activating alterations, and resistance mutations, showing ≥100-fold improved potency against ALKG1202R single and compound mutations over approved ALK TKIs. In vivo, it induces regression across 12 tumor models, including intracranial and patient-derived xenografts. NVL-655 inhibits ALK over TRK with 22-fold to >874-fold selectivity. These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion-positive non-small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers.©2024 The Authors; Published by the American Association for Cancer Research.