Abstract LB235: HP-001: A highly potent IKZF1/3 degrader that demonstrates superior safety profile

Abstract Introduction: Ikaros family zinc finger protein 1 and 3 (IKZF1/3) are essential transcription factors (TF) for the differentiation of B and T lymphocytes. IMiDs (e.g. pomalidomide, CC-220, CC-92480. etc) degrade IKZF1/3 via interaction with the cereblon (CRBN) E3 ligase and have shown promise in Multiple Myeloma (MM) and B-NHL. Enhanced IKZF 1/3 degradation would generally lead to improvement on both efficacy and toxicity. Here we presented HP-001, a highly potent IKZF1/3 degrader with improved efficacy and favorable safety profiles both in vitro and in vivo. Results: HP-001 demonstrated 5-fold improvement in CRBN binding and 10-fold improvement in IKZF1 degradation compared to CC-92480 in HTRF and K562-HiBiT-IKZF1 assays, respectively. The high IKZF1/3 degradation shown with HP-001 enabled potent antiproliferative activity across a panel of cancer cells (FL. MM, MCL, DLBCL, IC50 ranged from 0.01∼0.09 nM). In REC-1 and Mino MCL cells, after 24 h co-incubation, HP-001 (100 nM) demonstrated no degradation on other neo-substrates, e.g. SALL4, GSPT1, and CK1α, compared to >80% CK1α degradation in CC-92480 (100 nM) treatment. Additionally, HP-001 demonstrated 1000∼8000-fold optimized PBMC toxicity compared to CC-92480. In the H929 tumor xenograft model, administration of HP-001 (0.03 mpk, QD) promoted tumor regression (98% tumor growth inhibition by 15 days). On Day 21, the protein level of IKZF1/3 was measured by WB, indicating ∼80% and ∼70% degradation for HP-001 treatment group (0.03 mpk, QD) respectively, compared to ∼35% and ∼16% in CC-92480 group (0.03 mpk, QD). In mice bearing RPMI-8226 xenograft tumors, the combination of HP-001 (0.01 mpk, QD) and dexamethasone (5 mpk, QW) enabled complete tumor regression.Conclusions: HP-001 is a highly potent, catalytic degrader of IKZF1/3, with marked antitumor activity as a single agent and in combination with dexamethasone. HP-001 is currently in phase 1 clinical trial (CDE registration number: CTR20242943), a first-in-human, open-label, multicenter study to evaluate it as monotherapy in patients with r/r MM or NHL. Citation Format: Dihuang Wang, Jinhua Wu, Zheng Xu, Ting Peng, Kefeng Zhang, Liwen Zhao. HP-001: A highly potent IKZF1/3 degrader that demonstrates superior safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB235.