Advancements in CLL Treatment: ARQ 531 Outperforms Ibrutinib Against Wild Type and C481S Mutant BTK

ARQ 531 is an orally bioavailable, potent inhibitor of Bruton's tyrosine kinase (BTK) and other kinases, including Src and Tec family members. This compound presents a new option for treating chronic lymphocytic leukemia (CLL), especially for patients with the C481S mutation that confers resistance to ibrutinib. The compound's potency and binding kinetics have been evaluated in enzymatic assays and Surface Plasmon Resonance (SPR).

In CLL B cells, ARQ 531 treatment resulted in a significant reduction in viability at various concentrations compared to ibrutinib. The compound showed dose-dependent inhibition of BTK, AKT, and ERK phosphorylation, and it decreased the expression of activation markers CD40 and CD86 induced by CpG stimulation. ARQ 531 also reduced CLL cell migration towards CXCL12 and CXCL13, demonstrating its effect on cell activation and migration.

A key advantage of ARQ 531 is its ability to inhibit both wild type and C481S BTK with high potency, as shown in biochemical assays and its efficacy in cytotoxicity against CLL cells with C481S BTK mutations. The compound's residence time on BTK was measured in an SPR binding assay, indicating its binding kinetics.

In the TCL1 mouse model of CLL, ARQ 531 significantly improved survival and reduced lymphocyte counts more effectively than ibrutinib. Mice treated with ARQ 531 also showed increased absolute neutrophil counts over time, suggesting a potential restoration of granulocyte production.

The multi-targeted inhibition of cytokine, chemokine, and BCR pathways by ARQ 531 has proven effective in decreasing CLL cell activation, migration, and viability. Its activity against ibrutinib-resistant clones and its remarkable efficacy in the TCL1 model support the continued development of ARQ 531 and its potential transition to clinical trials.