9GBE

Structure of Human Anaplastic Lymphoma Kinase (ALK) harboring the G1202R/L1196M Compound Mutation in Complex with NVL-655

This is a non-PDB format compatible entry.

Summary for 9GBE

• Entry DOI: 10.2210/pdb9gbe/pdb
• Descriptor: ALK tyrosine kinase receptor, NVL-655 (3 entities in total)
• Functional Keywords: alk, tyrosine kinase inhibitor, resistance, nvl-655, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 39385.69

Authors

Mente, S.,Horan, J.C. (deposition date: 2024-07-31, release date: 2024-09-18, Last modification date: 2024-12-11)

Primary citation

Lin, J.J.,Horan, J.C.,Tangpeerachaikul, A.,Swalduz, A.,Valdivia, A.,Johnson, M.L.,Besse, B.,Camidge, D.R.,Fujino, T.,Yoda, S.,Nguyen-Phuong, L.,Mizuta, H.,Bigot, L.,Nobre, C.,Lee, J.B.,Yu, M.R.,Mente, S.,Sun, Y.,Kohl, N.E.,Porter, J.R.,Shair, M.D.,Zhu, V.W.,Felip, E.,Cho, B.C.,Friboulet, L.,Hata, A.N.,Pelish, H.E.,Drilon, A.
NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations.
Cancer Discov, 14:2367-2386, 2024

PubMed Abstract: 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.

PubMed: 39269178
DOI: 10.1158/2159-8290.CD-24-0231

Experimental method

X-RAY DIFFRACTION (1.58 Å)