Abstract
Abstract The clinical use of lenalidomide in multiple myeloma (MM), mantle cell lymphoma (MCL) and myelodysplastic syndromes (MDS) represents a significant advance in the treatment of hematological malignancies and has altered the landscape of the blood cancer therapy. Yet, many hematological indications and refractory diseases are still without effective systemic and curative therapies. Here we present KPG-818, a small molecule compound with high affinity binding to cereblon of the E3 ubiquitin ligase (CRBN-CRL4) complex, significantly inhibits the production of the pre-inflammatory cytokines such as TNF-α and IL-6 in LPS-stimulated human PBMC cells, inhibits HUVEC tube formation, and exhibits potent anti-proliferation in multiple lymphoma and multiple myeloma cell lines in vitro. Consistent with the finding in that lenalidomide causes selective degradation of Aiolos and Ikaros, KPG-818 potently inhibits the level of the two lymphoid transcription factors in MM1.S cell line model and human PBMC cells. In in vivo pharmacology studies, KPG-818 significantly inhibits tumor growth in MM.1S multiple myeloma, WSU-DLCL-2 diffuse large B cell lymphoma, DOHH-2 follicular lymphoma, REC-1 mantle cell lymphoma xenograft models. Importantly, KPG-818 prolongs the survival of the mouse cohorts bearing systemic human H929 multiple myeloma in a dose-dependent manner. Moreover, KPG-818 shows favorable DMPK and toxicity profiles in pre-clinical IND enabling studies. In summary, these immune modulation, anti-angiogenesis and antitumor results encourage the further clinical evaluation of KPG-818 in patients with Multiple Myeloma, Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Mantle Cell Lymphoma and other hematological malignancies. Citation Format: Chuansheng Ge, Baisong Liao, Lei Zhang. KPG-818, a novel cereblon modulator, inhibits hematological malignancies in preclinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6367.
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