Polyhedral alkanes as hydrophobic tags for dual-functional ALK inhibitor-degrader

To enhance the pharmacological activity of Brigatinib targeting anaplastic lymphoma kinase (ALK), we developed a 4D-QSAR model based on 49 Brigatinib derivatives. Model visualization suggested that introducing bulky hydrophobic groups at the piperazine moiety could enhance activity of Brigatinib, which aligned with the hydrophobic tagging (HyT) strategy. Based on this design principle, ten B-series compounds (B-1 to B-10) were designed, featuring two distinct types of hydrophobic tags: five conventional structures and five polyhedral alkanes (norbornane, adamantane, cubane, homocubane, and tetrahedrane). Cell proliferation assay in H3122 cells revealed that B-7 with norbornene tag (IC₅₀ = 68.98 nM), B-10 with tetraasterane tag (IC₅₀ = 97.77 nM), and B-6 with adamantane tag (IC₅₀ = 162.34 nM) outperformed Brigatinib (IC₅₀ = 222.35 nM), whereas B-9 with homocubane tag (IC₅₀ = 267.00 nM) showed comparable potency. According to ALK kinase inhibition assay, B-6, B-7, B-9, and B-10 retained potent ALK kinase inhibition (IC₅₀ = 0.74-1.24 nM), which were comparable to that of Brigatinib (IC₅₀ = 0.56 nM). Western blot assay revealed that both B-7 and B-10 were capable of effectively inducing ALK degradation. Molecular dynamics simulations suggested that the degraders induced ALK degradation by increasing the solvent-accessible surface area of hydrophobic residues near the binding pocket, inducing a partially unfolded conformation amenable to proteasomal degradation. ADMET predictions indicated that B-7 and B-10 exhibited favorable drug-like properties, superior to those of Brigatinib. This study not only identified B-7 and B-10 as promising dual-functional ALK inhibitor-degraders, but also enriched the structural diversity of hydrophobic tags through the introduction of novel polyhedral alkanes, particularly the norbornene and tetraasterane moieties.

4D-QSAR; ALK; Dual-functional inhibitor-degrader; HyT; Polyhedral alkanes.