Abstract 5121: PEG(E)-TC11, a novel polyethylene glycol-linked phthalimide derivative, inhibited high-risk MM cell growth in vivo and in vitro via cell cycle G2/M arrest in a CRBN-independent manner

Abstract

Multiple myeloma (MM) is one of the hematological malignancy that is characterized by proliferation of malignant plasma cells. Recent advance in the treatment of MM using newly developed drugs, prognosis of the MM patients have been significantly improved. For example, immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide and pomalidomide have been developed for treatment of MM. However, IMiDs have only limited effects against MM patients with high risk chromosomal abnormalities such as t(4;14) and del17p (high-risk MM). In 2010, it was reported that IMiDs directly bind to cereblon (CRBN), a component of ubiquitin ligase 3 complex, and induced teratogenicity as well as anti-tumor effects. We have previously reported that a novel phthalimide derivative, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3-dione (TC11) induced apoptosis against high-risk MM cells in vivo and in vitro, and inhibited differentiation of osteoclasts. We also reported that TC11 directly bound to α-tubulin and nucleophosmin-1 (NPM1), but did not bind to CRBN. However, TC11 was not well dissolved in water with only 0.02 mg/mL solubility. Therefore, TC11 showed poor absorption into blood and limited anti-tumor activity when it was intraperitoneally administered in tumor-bearing mice. To resolve these problems, we synthesized PEG(E)-TC11, in which TC11 is linked to polyethylene glycol through an ester bond, and consequently enhanced water solubility of PEG(E)-TC11 to 88.9 mg/mL. PEG(E)-TC11 revealed as potent growth inhibitory effect on high-risk MM cells as TC11 in vitro. In pharmacokinetic study, PEG-modification of TC11 improved the peak blood concentration (Cmax) from 2.6 to 24.4 μM and extended elimination half-life (t1/2) from 1.4 to 2.2 hr when 186 μM/kg of these compounds were intraperitoneally injected. More importantly, these pharmacokinetic improvement led to more potent growth inhibition of MM cells in vivo than TC11. We also explored mechanisms of anti-myeloma effect of PEG(E)-TC11 and found that PEG(E)-TC11 induced apoptosis via G2/M cell cycle arrest. However, unlike IMiDs family, BIACORE assay revealed that PEG(E)-TC11 didn’t directly bind to CRBN, indicating that growth inhibitory effect of PEG(E)-TC11 against MM cells was independent of binding to CRBN. In conclusion, PEGylation of TC11 significantly increased water solubility, resulted in potentiated anti-myeloma activity in vivo. Furthermore, PEG(E)-TC11 inhibited cell growth via G2/M arrest in a CRBN-independent manner. Thus, PEG(E)-TC11 is considered as a candidate compound for overcoming high-risk MM. Citation Format: Shuji Aida, Daiju Ichikawa, Kazuki Iida, Masashi Hozumi, Misa Nakamura, Ryo Uozaki, Nahoko Hashimoto, Mikio Okayama, Yuko Yonemura, Noriko Tabata, Taketo Yamada, Maiko Matsushita, Takeshi Sugai, Hiroshi Yanagawa, Yutaka Hattori. PEG(E)-TC11, a novel polyethylene glycol-linked phthalimide derivative, inhibited high-risk MM cell growth in vivo and in vitro via cell cycle G2/M arrest in a CRBN-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5121. doi:10.1158/1538-7445.AM2017-5121