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.

免疫调节药物（Immunomodulatory drugs, IMiDs）是血液系统恶性肿瘤中广泛应用的治疗手段，但其临床应用常受限于耐药性。本研究通过对多种cereblon（CRBN）结合剂的筛选、全面的构效关系（structure–activity relationships, SAR）分析以及系统性降解谱表征，发现MGD-22作为一款以酞嗪酮为骨架的强效IKZF1/2/3降解剂：其在多发性骨髓瘤（multiple myeloma, MM）、急性髓系白血病（acute myeloid leukemia, AML）及弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma, DLBCL）等多种血液癌细胞系中均展现出纳摩尔级的IC₅₀活性，且可克服对泊马度胺的获得性耐药。MGD-22可通过依赖Cullin-CRBN通路（Cullin-CRBN pathway）的方式，选择性强效降解IKZF1/2/3，其DC₅₀活性亦达纳摩尔级别。进一步研究显示，口服给药的MGD-22具备优异的药代动力学特性，可显著抑制肿瘤生长；且分别与布鲁顿酪氨酸激酶（Bruton’s tyrosine kinase, BTK）及B细胞淋巴瘤-2（B-cell lymphoma-2, BCL-2）抑制剂联用时，在DLBCL细胞中展现出显著的协同抗肿瘤效应。综上，本研究确立了IKZF1/2/3三靶点降解的理论依据，并将MGD-22定位为一款在血液系统恶性肿瘤治疗中具有广阔应用前景的候选治疗药物。