Abstract 513: Preclinical evaluation of novel HDAC6 selective inhibitors CVL608 with potent <i>in vitro</i> and <i>in vivo</i> profiles in tumors
Authors: Zeng Li, Yaobang Cheng, Xiaokun Shen, Yonghui Wang
Journal: Cancer Research (2020)

Abstract HDAC inhibitors are an emerging class of anticancer agents with the approved indications of multiple myeloma, cutaneous and/or peripheral T cell lymphoma. However, non-selective pan-HDAC inhibitors are often reported associated with heart, hematologic and gastrointestinal toxicities. Among HDAC subtypes, inhibiting HDAC6 selectively may not only enhance potency, but may also reduce the toxicity related to off-target effects of pan-HDACis. In previous studies, pioneer HDAC6 selective inhibitors have been demonstrated with the potential to treat both non-solid tumor and solid tumors along or in combination with chemotherapy, proteasome inhibitors or checkpoint inhibitors. In this work, we report the design, in vitro and in vivo evaluation a class of novel HDAC6 selective inhibitors, series CVL608, with potent antitumor profiles in non-solid tumor such as multiple myeloma, and solid tumors including breast cancer, melanoma and NSCLC. Method:1.The HDAC enzymes inhibition screening were performed using HDAC Caliper assay, 12-sipper chip and Caliper EZ Reader II systems.2.The anti-proliferative effects of compounds were assessed in variety cancer cell lines including MM.1S, REC-1, Mino, SK-MEL-5, A375, MCF-7, A549 and OVCAR-3 by quantifying cell proliferation by standard CellTiter-Glo® assay after a 72-h incubation.3.The in vivo efficacy of compounds as monotherapy and in combination with chemotherapy and proteasome inhibitors were examined in MM.1s and MCF-7 CDX models in BALB/c nude mice (n=6/group); compounds in combination with checkpoint inhibitors were examined in LL/2(LLC1) and B16F10 CDX models in C57BL/6 mice (n=6/group). Conclutions:1.According to the HDAC Caliper assay, CVL608 series compounds were identified as HDAC6 selective inhibitors bearing 5-20X selectivity over HDAC3, 20-100X selectivity over HDAC1 and HDAC8, with the HDAC6 potency upto less than 5 nM. The compounds exhibited a priority selectivity than clinical candidates ACY-1215 and ACY-241.2.Lead compounds CVL608 inhibited MM.1S, REC-1, Mino, SK-MEL-5, A375, MCF-7, A549 and OVCAR-3 with the IC50 less than 10 micromole, which were equal or better compared with ACY-241.3.In MM.1s CDX models, lead compounds CVL608 was more potent than ACY-241 at 30mg/kg in tumor proliferation as monotherapy. Moreover, CVL608 in combination with Bortezomib (0.5 mg/kg) significate inhibit tumor growth compared with monotherapy and ACY-241+Bortezomib (p&amp;lt;0.05). CVL608 monotherapy and in combination with PTX in MCF-7 CDX, and in combination with PD-1 inhibitor in LL/2(LLC1) and B16F10 CDX models are under investigating.These data may support interest in the clinical development of novel HDAC6 selective inhibitors in both non-solid tumor and solid tumors. Citation Format: Zeng Li, Yaobang Cheng, Xiaokun Shen, Yonghui Wang. Preclinical evaluation of novel HDAC6 selective inhibitors CVL608 with potent in vitro and in vivo profiles in tumors [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 513.