Discovery of an ALK degrader for lorlatinib-resistant compound mutations

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Advanced generations of ALK tyrosine kinase inhibitors (TKIs) show success in ALK-rearranged non-small cell lung cancer (NSCLC).
• Acquired resistance mutations following ALK TKI therapy present a major clinical challenge.
• Specific mutations like G1202R/L1196M confer resistance to existing therapies, including lorlatinib.

Purpose of the Study:

• To identify novel ALK inhibitors capable of overcoming acquired resistance mutations.
• To design and evaluate a Proteolysis Targeting Chimera (PROTAC) molecule for enhanced ALK degradation.
• To assess the efficacy of the novel compounds in preclinical models of ALK-driven NSCLC.

Main Methods:

• Identification and characterization of WZH-15-125 as a potent ALK inhibitor.
• Design and synthesis of WZH-17-002, an ALK-targeting PROTAC molecule utilizing WZH-15-125 as the warhead.
• In vitro assessment of ALK protein degradation by WZH-17-002, including determination of DC50 values.
• In vivo efficacy studies using xenograft mouse models harboring specific ALK resistance mutations.

Main Results:

• WZH-15-125 demonstrated potent inhibition of ALK, including resistance mutations like G1202R/L1196M.
• WZH-17-002 efficiently degraded ALK proteins with a DC50 of 25 nM.
• WZH-17-002 suppressed the emergence of drug resistance and exhibited superior in vivo efficacy compared to lorlatinib in relevant models.

Conclusions:

• WZH-15-125 and its PROTAC derivative WZH-17-002 represent promising therapeutic strategies against ALK-rearranged NSCLC with acquired resistance.
• The developed ALK PROTAC molecule offers a potential approach to overcome challenging resistance mutations, including those resistant to lorlatinib.
• These findings support further development of WZH-17-002 for clinical application in treating refractory ALK-driven NSCLC.