lorlatinib

Lorlatinib (PF-6463922) is an orally available, ATP-competitive inhibitor of the receptor tyrosine kinases, anaplastic lymphoma kinase (ALK) and C-ros oncogene 1 (Ros1), with potential antineoplastic activity.

WZH-15-125 is a potent ALK inhibitor capable of overcoming resistance, particularly with complex ALK mutations. It exhibits an IC50 of 101.7 nM against the highly recalcitrant Lorlatinib-resistant G1202R/L1196M mutation. Additionally, WZH-15-125 can serve as a PROTAC target protein ligand for synthesizing PROTACWZH-17-002. This compound is applicable in non-small cell lung cancer research.

WZH-17-002 is an ALKPROTAC degrader based on WZH-15-125, with a DC50 of 25 nM. This compound enhances the efficacy against ALK mutations that confer resistance to Lorlatinib. Moreover, WZH-17-002 significantly reduces resistance in ALK fusion non-small cell lung cancer (NSCLC) and inhibits tumor growth in EML4-ALK G1202R/L1196M xenograft mouse models.