Abstract 2919: Discovery of PRT811, a potent, selective, and orally bioavailable brain penetrant PRMT5 Inhibitor for the treatment of brain tumors
Authors: Zhang Yang , Lin Hong , Wang Min , Angelis Dimitrios , Hawkins Michael , Rominger Dave , Emm Tom , Luengo Juan , Ruggeri Bruce , Scherle Peggy , Vaddi Kris 
Published: September 2020

Abstract
Protein arginine methyltransferase 5 (PRMT5) is the major type II PRMT that catalyzes the formation of symmetrical dimethyl arginine (SDMA) on protein substrates and plays important roles in regulating RNA splicing as well as transcription and activity of critical oncogenic signaling pathways. Recent studies have revealed PRMT5 as a potential therapeutic target for various cancers including Central Nervous System (CNS) tumors such as glioblastoma (GBM), the most common and aggressive primary brain tumor in adults. Several PMRT5 inhibitors have entered into the clinic for hematological and solid tumors, but none have been reported to be brain penetrant, a potentially desirable feature of a small molecule designed for treating CNS cancers and brain metastases.
PRT811 is a potent, selective, and brain penetrant PRMT5 inhibitor, and exhibits potent in vitro and in vivo activities in preclinical models of brain tumors. PRT811 inhibited the methyltransferase activity of the PRMT5/MEP50 complex with an IC50 of 3.9 nM, but showed minimal inhibition against a panel of 37 human methyltransferases at 10 µM. In a panel of brain cancer cell lines of varied histology, PRT811 reduced SDMA levels and inhibited cell proliferation with IC50 values in the range of 7-40 nM and 29-134 nM, respectively, regardless of expression levels of methylguanine methyltransferase (MGMT), the expression of which is associated with temozolomide (TMZ) resistance. Furthermore, PRT811 demonstrated broad antiproliferative activity in a panel of 87 cell lines consisting of brain, breast, lung, and skin cancers, representing primary and the most common cancer types that metastasize to the brain. Finally, PRT811 effectively inhibited cell growth in a panel of patient derived xenograft models of GBM in ex vivo 3D cultures.
PRT811 is a highly permeable molecule with high brain penetrance in rodents, with an efflux ratio &lt;1 and brain/plasma ratio ranging from 2 to 5 in mice. In vivo, oral administration of PRT811 in nude mice bearing U-87 MG human GBM orthotopic xenografts reduced tumor SDMA levels by ~50% but had no effect on SDMA in normal brain cells, as assessed by immunohistochemistry (IHC). Moreover, in a U-87 MG subcutaneous xenograft model in nude rats, once daily oral dosing of PRT811 at 20 and 30 mg/kg resulted in 91% and 100% tumor growth inhibition, respectively. PRT811 and related analogues are being studied across a panel of primary human and murine brain tumors ex vivo, and in vivo in primary orthotopic models of CNS lymphoma, a rare and aggressive subset of non-Hodgkins lymphomas.
PRT811 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors, gliomas, and myelofibrosis (NCT04089449).
Citation Format: Yang Zhang, Hong Lin, Min Wang, Dimitrios Angelis, Michael Hawkins, Dave Rominger, Tom Emm, Juan Luengo, Bruce Ruggeri, Peggy Scherle, Kris Vaddi. Discovery of PRT811, a potent, selective, and orally bioavailable brain penetrant PRMT5 Inhibitor for the treatment of brain 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 2919.