Design, synthesis, and biological evaluation of novel 1-aryl-3-hydroxypyrrolidine derivatives as dual HGK/HPK1 inhibitors with therapeutic potential for lung cancer.

Recent research certified that HGK, as an upstream regulator of the MAPK/ERK signaling pathway, represents a promising target for lung cancer therapy. Herein, in pursuit of novel HGK inhibitors, a series of 1-aryl-3-hydroxypyrrolidine derivatives were designed and synthesized based on the hit compound Z1, which was obtained via high-throughput screening. Through comprehensive biological evaluation, Z7 was identified as the optimal compound with potent enzymatic (HGK IC50 = 0.047 μM) and cellular activities (H460 IC50 = 1.42 μM). Notably, Z7 also demonstrated marked inhibition against HPK1 (IC50 = 0.065 μM) in selectivity assessment, positioning it as a dual HGK/HPK1 inhibitor. Moreover, Z7 exhibited favorable selectivity across a panel of 80 kinases and pronounced in vivo anti-lung cancer efficacy (TGI = 68.94% at 20 mg/kg dosage) in H460 xenograft models. Overall, our findings suggest that dual targeting of HGK and HPK1 represents a viable therapeutic strategy for lung cancer.