Abstract 1128: Selective, novel, small molecule PRMT5 inhibitors for treatment of cancer
Authors: Sivanandhan Dhanalakshmi , Rajagopal Sridharan , M Naveen Sadhu , Gajendran Chandru , Vadivelu Saravanan , Tamizharasan Natarajan , Swamy Indu N. , Viswakarma Santhosh , Siddiqui Amir , wahid Saif , Zainuddin Mohammed , G Rudresh , Daram Prashanthi , Gosu Ramchandraiah , Tiagaraj Dinesh , Garapaty Shivani , Nair Sreekala , Kapoor Namratha 
Published: July 2021

Introduction: Arginine methylation deregulation in cancer has been well studied and PRMT5 which modulates dimethylation of arginine has emerged as an attractive therapeutic strategy in various cancer types, including lung cancer, lymphoma, glioblastoma, pancreatic cancers, etc. PRMT5 is over-expressed in multiple cancers leading to repression of tumor suppressor genes and genetic studies have identified it is a validated target in lymphoma. Recently, dysregulation of the splicing machinery in cancers has been identified to be one of the therapeutic vulnerabilities for PRMT5 inhibition, especially in glioblastoma. Therefore, inhibitors selectively targeting PRMT5 could be of high clinical value, especially in cancers with defects in spliceosome machinery.

Methods: Rational design and structure based drug design were used to identify novel PRMT5 inhibitors. To assess in vitro potency, flash plate based activity assay was used. Cell based activity of these inhibitors was assessed by measuring the symmetrical dimethylation of known cellular protein SmD3 by ELISA and Western blotting. Long term cell proliferation assays were used to assess the functional effect of PRMT5 inhibition. Tumor growth inhibition was measured in orthotopic glioblastoma model in mice.

Results: One of the lead PRMT5 inhibitors had an in vitro potency of 3 nM in the biochemical assay which translated well in the cell based SDMA ELISA where the EC50 was &lt;10 nM. Anti-proliferative activity of this molecule in lymphoma, leukaemia, SCLC, pancreatic, lung and glioblastoma cell lines ranged from ~16 nM to 1035 nM. This molecule showed acceptable in vitro ADME properties in terms of aqueous solubility and metabolic stability and excellent oral bioavailability in rodent pharmacokinetics. In Z-138 mantle cell lymphoma xenograft model, oral administration of the lead compound at 50 mg/kg resulted in strong and complete (~95 %) tumour growth inhibition and with a concomitant complete inhibition of SDMA. The lead compound was well tolerated with no reduction in body weight at the tested doses. Interestingly, this molecule showed excellent brain exposure sufficient to achieve target engagement for 10h and significant tumour growth inhibition of orthotopic brain tumors by oral dosing. Repeat dose non-GLP study in rodents clearly demonstrated the safety of this molecule.

Conclusion: Given the therapeutic importance of PRMT5 in glioblastoma and other lymphomas, this molecule will be extremely valuable in treating these cancers both as a standalone therapy and in combination with other standard of care agents.

Citation Format: Dhanalakshmi Sivanandhan, Sridharan Rajagopal, Naveen Sadhu M, Chandru Gajendran, Saravanan Vadivelu, Natarajan Tamizharasan, Indu N. Swamy, Santhosh Viswakarma, Amir Siddiqui, Saif wahid, Mohammed Zainuddin, Rudresh G, Prashanthi Daram, Ramchandraiah Gosu, Dinesh Tiagaraj, Shivani Garapaty, Sreekala Nair, Namratha Kapoor. Selective, novel, small molecule PRMT5 inhibitors for treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1128.