Is there a fourth generation of resistance to lorlatinib/lorlatinib?

Lorlatinib/lorlatinib (Lorlatinib) is a potent third-generation ALK inhibitor capable of overcoming resistance to first- and second-generation ALK inhibitors, including resistance mediated by the G1202R mutation, and has significant activity against brain metastases. Clinical responses to lorlatinib were observed in 39% of patients who had previously received two or more ALK inhibitors, with a median PFS of 6.9 months. Although next-generation (lorlatinib)ALK TKIs have higher kinase selectivity and greater ability to resist resistance, it has been proven that treatment resistance still inevitably emerges after a certain period of time after starting the drug.

Research shows that about35% of acquired resistance to lorlatinib mechanism is attributed to compound mutations. Recent studies have shown that 6 of the 14 compound mutations are sensitive to first- or second-generation ALK TKI inhibitors. However, approximately 50% of compound mutations are resistant to every ALK TKI drug currently on the market. Notable examples of such resistance mutations include combinations such as G1202R+F1174C, G1202R+F1174L, and G1202R+L1196M.

Turning Point Therapeutics recently developedTPX-0131 (zotizalkib) and repotrectinib (TPX-0005), two tiny, compact macrocyclic compounds. Both compounds have lower molecular weights than currently FDA-approved ALK TKIs. These two compounds are classified as fourth-generation ALK TKIs because of their high potency against various resistance mutations to lorlatinib. No previous computational studies have delved into the exact impact of the F1174C/L/V mutation on the binding process of the fourth-generation drugs TPX-0131 and repotrectinib to the third-generation drug lorlatinib.