Targeting drug-resistant mutations in ALK

Abstract

Therapy resistance limits the clinical success of tyrosine kinase inhibitors (TKIs) in ALK-positive non-small cell lung cancer. A study now proposes a framework to identify compound resistance mutations to the lorlatinib TKI and provides structure-based drug design approaches to overcome resistance mediated by ALK(G1202R) or ALK(I1171N/S/T).

Fig. 1 |

Mechanism of ALK compound mutations and inhibition by LA9 and LA7. a, Classification and functional characterization of mutations in EML4–ALK that drive resistance to active site TKIs, including lorlatinib, has led to the development of analogs LA9 and LA7 that inhibit G1202R- and I1171N-based compound mutations, respectively. b, 2D depiction of the macrocyclic inhibitor loratinib, and the more flexible acyclic analogs LA9 and LA7, highlighting crucial binding contacts in ALK including at the G1202R solvent-front position and the I1171N alteration at the base of helix αC and directly adjacent to the gatekeeper residue L1196.