Abstract 4856: Novel, small-molecule PRMT5 inhibitors for treatment of cancer
Authors: Sivanandhan Dhanalakshmi , Garapaty Shivani , Vadivelu Saravanan , Seerapu Guru Pavan Kumar , Das Reshma , Kar Ronodip , Singh Anuj Kumar , Venkateshappa Venkatesha Ashokkumar , Tamizharasan Natarajan , Swamy Indu N. , Nagaraju Nagendra , Kanagaraj Subramaniyam , Sarkar Sayanti , Tibhe Jagadish D. , G Rudresh , Zainuddin Mohd , Kandan Saravanan , Rajagopal Sridharan , Rajagopal Sriram 
Published: August 2018

Abstract
Arginine methylation deregulation in cancer has been well studied and PRMT5, a modulator of symmetric dimethylation of arginine (SDMA) has emerged as an attractive therapeutic strategy in various cancer types. PRMT5 is highly expressed in several cancers, including ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, bladder cancers and germ cell tumors. PRMT5 over-expression is thought to be an important factor in its tumorigenicity due to its repressive function on the expression of tumor suppressor genes. Therefore, PRMT5 has emerged as a therapeutic target and inhibitors selectively targeting PRMT5 could be of high clinical value. Rational design and structure based drug design were used to identify novel PRMT5 inhibitors. FlashPlate® methylation assay was used to assess in vitro potency. Cell based activity of these inhibitors was assessed by measuring the symmetrical dimethylation of known cellular protein SmD3. Long term cell proliferation assays were used to assess the functional effect of PRMT5 inhibition. A number of compounds from two different series showed strong in vitro potency against PRMT5, which were comparable to the reported GSK inhibitor. Multiple co-crystal structures have been solved in-house and are extensively used in optimization of these novel scaffolds. Their cell based potency, as measured by proliferation assay in multiple haematological and solid tumor cell lines was comparable to biochemical potency. JBI-778, from one of the series showed an in vitro potency of 0.0.045 μM (0.110 µM for GSK) and 0.005 µM in inhibiting SmD3 dimethylation. JBI-778 exhibited an GI50 of 0.01 to 1 µM in inhibiting proliferation of lymphoma cell lines, whereas the GI50 in other solid tumor cell lines PDAC, SCLC, GBM were in the range of 0.02 to 1.5 µM, again comparable (or better) than the GSK inhibitor. JBI778 showed good in vitro ADME properties in terms of aqueous solubility and metabolic stability and reasonable oral bioavailability in mouse pharmacokinetics. In Z-138 xenograft model, oral administration of JBI-778 at 50 mg/kg resulted in stronger and complete (~90%) tumor growth inhibition and was tolerated well. At comparable dose, this tumor growth inhibition was better than the GSK inhibitor. In addition, JBI-778 showed reasonable brain exposure sufficient to achieve biomarker modulation in brain. SAR has clearly demonstrated that there is further scope to optimize this series for potency, properties and brain exposure. Further studies are underway to better understand the therapeutic potential of these PRMT5 inhibitors in a number of solid cancers including PDAC, SCLC and GBM. Given the therapeutic importance of PRMT5 in Glioblastoma, these molecules will be extremely valuable in treating this cancer either as standalone therapy or in combination with other standard of care agents.
Citation Format: Dhanalakshmi Sivanandhan, Shivani Garapaty, Saravanan Vadivelu, Guru Pavan Kumar Seerapu, Reshma Das, Ronodip Kar, Anuj Kumar Singh, Venkatesha Ashokkumar Venkateshappa, Natarajan Tamizharasan, Indu N. Swamy, Nagendra Nagaraju, Subramaniyam Kanagaraj, Sayanti Sarkar, Jagadish D. Tibhe, Rudresh G, Mohd Zainuddin, Saravanan Kandan, Sridharan Rajagopal, Sriram Rajagopal. Novel, small-molecule PRMT5 inhibitors 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 4856.