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 <b>LP46</b> emerged as a lead candidate, exhibiting remarkable potency (IC₅₀ = 7.5 nM against IKKβ) and exceptional kinome selectivity. <b>LP46</b> effectively suppressed cell viability and proliferation in RKO and HCT116 human colorectal cancer cell lines. Mechanistic investigations revealed that <b>LP46</b> inhibited IKKβ phosphorylation, thereby attenuating NF-κB signaling while simultaneously inducing autophagy. In vivo studies further demonstrated that <b>LP46</b> possesses favorable pharmacokinetic properties, including high oral bioavailability (<i>F</i> = 34.08%), a suitable half-life (<i>T</i>_1/2 = 3.261 h), and robust metabolic stability. Importantly, <b>LP46</b> effectively suppressed tumor growth in RKO and MC38 xenograft mouse model and in MC38-derived syngeneic model, with no obvious toxicity, demonstrating that <b>LP46</b> could be developed as potential novel therapeutic for colorectal cancer treatment.