Abstract 1756: JBI-802, novel dual inhibitor of LSD1-HDAC6 for treatment of cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.1756-1756
• Main Authors: Sivanandhan, Dhanalakshmi, Rajagopal, Sridharan, Nair, Sreekala, B, Basavaprabhu, Dhkar, Reshma, Viswakarma, Santosh, Siddiqui, Amir, Zainuddin, Mohd, G, Rudresh, Daram, Prashanthi, Mohire, Sunil, V, Krishnakumar
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-1756

Introduction: Lysine Specific Demethylase 1 (LSD1) is over-expressed in many cancers and down-regulation of LSD1 has been shown to effectively treat cancers by inducing re-expression of aberrantly silenced genes. Studies have shown that LSD1 may contribute to acute myelogenous leukaemia pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML. In addition, LSD1 inhibition also leads to convertion of ‘cold' tumors to ‘hot' tumors by activating type 1 interferon response. Similarly, HDAC6 inhibition enhances immune response by over-coming immune suppression. Further, combined inhibition of LSD1 and HDAC has been shown to be more efficacious in inhibiting multiple cancers. Here, we show that JBI-802, a dual inhibitor targeting both LSD1 and HDAC6/8 shows stronger efficacy in several cancers, including AML, lymphoma and others and well tolerated at efficacious doses. Methods: Computational chemistry approaches were used to design LSD1 specific and LSD1-HDAC dual inhibitors. To assess in vitro LSD1 potency, TR-FRET assay was used. For assessing in vitro HDAC activity fluorescence based HDAC6 activity assay was performed. Western blotting and quantitative PCR were used to assess biomarkers of LSD1 and HDAC inhibition. Alamar blue cytotoxicity assay was used to assess cell proliferation. Xenograft and syngeneic models were used to assess in vivo efficacy. Results: Several compounds from this series show strong in vitro potency against LSD1 with excellent selectivity against MAOs. JBI-802 our lead dual molecule, showed an IC50 of 0.05 μM against LSD1 and isoform selective HDAC6/8 activity (IC50 of 0.011 and 0.098 µM on HDAC6 and HDAC8, respectively), with about 100 fold selectivity against other HDAC isoforms. When assessed in a panel of 25 cell lines, JBI-802 showed strong anti-proliferative activity on select AML, CLL, SCLC, sarcoma and multiple myeloma cell lines. In cell based and in vivo target engagement studies there was significant dose-dependent increase in CD11b, CD86 and GFI1b and tubulin acetylation levels. JBI-802 had a much stronger effect in inhibiting the growth of HEL92.1.7 erythroleukemia xenograft by oral administration when compared to ACY-1215, a HDAC6 selective inhibitor or ORY-1001 an LSD1 selective inhibitor. ED50 of JBI-802 in this model was ~6.25 mg/kg BID. Further, dose-dependent modulation of above mentioned biomarkers and inhibition of c-Myc could be observed in