Abstract 1382: Novel dual inhibitors of LSD1-HDAC6/8 for treatment of cancer
Authors: Dhanalakshmi Sivanandhan , Rajagopal Sridharan , Nair Sreekala , Gajendran Chandru , Ghosh Dimpy , Tantry Subramanyam Janardhan , Dewang Purushottam , Hallur Mahanandeesha , Kannan M , KC Srinatha , Kuntrapaku Damodara , Dilipkumar M , Sharma Radha , Meghashree S , Kumar D P. , Zainuddin Mohd , Vinod A B. , Rajagopal Sriram 
Published: August 2018

LSD1 is an FAD-dependent amine oxidase that removes methyl groups from mono- or dimethylated histone H3 lysine 4 (H3-K4) as a part of CoREST repressor complex. Recent studies have shown that there is crosstalk between two components of CoREST complex, LSD1 and HDAC, which provides an advantage to cancer cell proliferation and survival by regulating key signaling pathways. Accordingly, combined inhibition of LSD1 and HDAC has been shown to be more efficacious in inhibiting the growth of glioblastoma, AML and breast cancer. Therefore, dual inhibitors targeting both LSD1 and HDAC could be useful in treating several cancers effectively without enhancing systemic toxicity mediated by administration of multiple drugs. To test the hypothesis, we have developed a set of molecules that either have LSD1 activity alone or dual activity on LSD1 and HDAC. Computational chemistry approaches were used to design LSD1-HDAC dual inhibitors. In vitro LSD1 potency was assessed by TR-FRET assay and in vitro HDAC activity by fluorimetric HDAC activity assay. Western blotting and RT qPCR were used to assess biomarkers of LSD1 and HDAC inhibition. Alamar blue cytotoxicity assay was used to assess cell proliferation. Multiple compounds from this series show an in vitro potency of less than 0.05 μM against LSD1 with more than 100-fold selectivity against MAOs. The dual inhibitors showed stronger activity on HDAC6/8. JBI-097, one such dual molecule with LSD1/HDAC/6/8 selectivity, showed an IC50 of 0.007uM on LSD1 and an IC50 of 0.06 and 0.1uM on HDAC6 and HDAC8, respectively, with about 100-fold selectivity against other HDAC isoforms. JBI-097 showed strong antiproliferative activity on leukemia and multiple myeloma cell lines. In MM.1S cell line, JBI-097 showed stronger potency when compared to LSD1 inhibitor GSK2879552 and HDAC6 inhibitor ACY1215. In cell-based and in vivo target engagement studies there was a concomitant increase in CD11b, CD86 and GFI1b and tubulin acetylation levels. JBI-097 was more efficacious in inhibiting the growth of HEL92.1.7 xenograft by oral administration when compared to IP administration of an HDAC inhibitor. In MM.1S tumor model, JBI-097 showed stronger effect in inhibiting tumor growth when compared to LSD1 inhibitor and HDAC6 inhibitor used as single agents. Further, combination with topotecan resulted in complete tumor growth inhibition of MM.1S xenograft. The data obtained demonstrate that it is feasible to design dual LSD1-HDAC6/8 inhibitors that retain individual activity and potently inhibit cell proliferation, and such inhibitors could serve as powerful therapeutic agents for cancer. Further understanding of mechanisms to identify the right tool compound is in progress.

Citation Format: Sivanandhan Dhanalakshmi, Sridharan Rajagopal, Sreekala Nair, Chandru Gajendran, Dimpy Ghosh, Subramanyam Janardhan Tantry, Purushottam Dewang, Mahanandeesha Hallur, M Kannan, Srinatha KC, Damodara Kuntrapaku, M Dilipkumar, Radha Sharma, S Meghashree, D P. Kumar, Mohd Zainuddin, A B. Vinod, Sriram Rajagopal. Novel dual inhibitors of LSD1-HDAC6/8 for treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1382.