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, MGD-22, a potent IKZF1/2/3 degrader featuring a phthalazinone
scaffold, demonstrated nanomolar-range IC50 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. MGD-22 selectively induced robust degradation
of IKZF1/2/3 in a Cullin-CRBN pathway-dependent manner, with nanomolar
DC50 potency. Furthermore, orally administered MGD-22 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 MGD-22 as a promising therapeutic
candidate with broader applicability in hematological cancer treatment.