Discovery and Structural Optimization of Novel 2-Aminopyrimidine Derivatives as Potent and Selective IKKβ Inhibitors for the Treatment of Colorectal Cancer.

The IκB kinase β (IKKβ)-mediated NF-κB signaling pathway plays a critical role in colorectal cancer progression. We designed and synthesized a novel series of 2-aminopyrimidine derivatives as selective IKKβ inhibitors. Among them, compound LP46 emerged as a lead candidate, exhibiting remarkable potency (IC50 = 7.5 nM against IKKβ) and exceptional kinome selectivity. LP46 effectively suppressed cell viability and proliferation in RKO and HCT116 human colorectal cancer cell lines. Mechanistic investigations revealed that LP46 inhibited IKKβ phosphorylation, thereby attenuating NF-κB signaling while simultaneously inducing autophagy. In vivo studies further demonstrated that LP46 possesses favorable pharmacokinetic properties, including high oral bioavailability (F = 34.08%), a suitable half-life (T1/2 = 3.261 h), and robust metabolic stability. Importantly, LP46 effectively suppressed tumor growth in RKO and MC38 xenograft mouse model and in MC38-derived syngeneic model, with no obvious toxicity, demonstrating that LP46 could be developed as potential novel therapeutic for colorectal cancer treatment.