Targeted protein degradation of neosubstrates plays a crucial role in treating hematological cancers with IMiDs therapy. However, the inevitable drug resistance and hematological toxicities remain persistent challenges, limiting their clinical efficacy. Herein, we present the discovery of a lead degrader with a novel phthalazinone scaffold, termed I-4, which targets Ikaros family proteins. Through molecular dynamic-based drug design and unbiased proteomics analysis, we further developed a novel candidate, I-8, that significantly inhibited the growth of hematological cancer cells and induced the degradation of Ikaros family proteins and casein kinase 1α (CK1α) with nanomolar potency via a Cullin-CRBN dependent pathway. To further investigate the global protein degradation of neosubstrates induced by our degraders, we performed a quantitative proteomics analysis in cells treated with I-4/I-8, pomalidomide and CC-220. Additionally, to further explore the mechanisms underlying IMiDs resistance, we conducted proteomics analyses in cells with acquired resistance.