Discovery of Novel Potent Triple IKZF1/2/3 Degraders for the Treatment of Hematological Cancers.

Immunomodulatory drugs (IMiDs) are widely utilized therapies in multiple hematological cancers; however, their clinical application is frequently constrained by drug resistance. Here, though screening of diverse cereblon (CRBN) binders, comprehensive structure-activity relationships (SAR) analyses and systematic degradation profiling, , a potent IKZF1/2/3 degrader featuring a phthalazinone scaffold, demonstrated nanomolar-range IC potencies across diverse multiple myeloma (MM), acute myeloid leukemia (AML), and diffuse large B-cell lymphoma (DLBCL) cancer cells and overcame acquired resistance to pomalidomide. selectively induced robust degradation of IKZF1/2/3 in a Cullin-CRBN pathway-dependent manner, with nanomolar DC potency. Furthermore, orally administered demonstrated significant tumor growth inhibition with admirable pharmacokinetic properties and displayed s marked synergistic effects with Bruton's tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitor, respectively, in DLBCL cancer cells. Collectively, these findings establish a rationale for triple-targeted degradation of IKZF1/2/3 and position as a promising therapeutic candidate with broader applicability in hematological cancer treatment.