Discovery of an ALK degrader for lorlatinib-resistant compound mutations.

Three generations of ALK tyrosine kinase inhibitor (ALK TKI) have achieved significant clinical success in the treatment of ALK rearranged non-small cell lung cancer (NSCLC). However, the emergence of acquired mutations after sequential ALK TKI therapies poses significant challenges for cancer treatment. Here we identified WZH-15-125 as a potent ALK inhibitor that can effectively override drug resistance, especially compound ALK mutations, including the highly refractory G1202R/L1196M mutation that is resistant to lorlatinib. By using WZH-15-125 as the warhead, we designed an ALK PROTAC molecule WZH-17-002 that can efficiently degrade ALK proteins with half maximal degradation concentration (DC) values of 25 nM. Furthermore, WZH-17-002 suppresses the emergence of drug resistance and exhibits superior in vivo pharmacological efficacy than lorlatinib in ALK G1202R/L1196M xenograft mouse models. These findings suggest a potential strategy for overcoming resistance to ALK TKI therapies.