PRMT5 is a type II methyltransferase that symmetrically di-methylates arginine residues on proteins involved in signal transduction and cellular transcription. For example, PRMT5 acts as the enzymatic machinery of the methylosome complex, crucial for spliceosome assembly and activity. Although not frequently mutated or amplified in tumors, an elevated PRMT5 protein level that leads to higher methylosome activity and promotes epithelial–mesenchymal transition, has recently been correlated with a poor survival of cancer patients. The PRMT5 inhibitor JNJ-64619178 has been selected as a clinical candidate based on its high selectivity and potency, paired with favorable oral pharmacokinetics and safety properties. JNJ-64619178 binds simultaneously to the SAM- and protein substrate- binding pockets of the PRMT5/MEP50 complex with a pseudo-irreversible mode-of-action. Chemical proteomics, methylomics and RNA-sequencing analyses of PRMT5 inhibitor treated cell line samples support the current biological understanding of PRMT5 as a regulator of alternative splicing events. JNJ-64619178 showed potent and broad inhibition of cellular growth, observed in several cell line panels that represent diverse cancer histologies. Ongoing investigations will explore the potential synthetic lethal correlation between PRMT5 inhibition and cancer driver pathways, including those addicted to altered splicing. Oral administration of JNJ-64619178 resulted in efficient inhibition of di-methylation of SMD1/3 proteins, components of the splicing machinery and direct substrates of the methylosome, in several human NSCLC and SCLC cancer mouse xenograft models. JNJ-64619178 demonstrated dose-dependent tumor growth inhibition and regression in several human NSCLC and SCLC cancer mouse xenograft models with sustained blockage of tumor re-growth after dosing cessation. In summary, JNJ-64619178 has a favorable pre-clinical profile supporting clinical testing in patients with lung cancer and other malignancies. Citation Format: Tongfei Wu, Hillary Millar, Dana Gaffney, Lijs Beke, Geert Mannens, Petra Vinken, Ivan Sommers, Jan-Willem Thuring, Weimei Sun, Christopher Moy, Vineet Pande, Junguo Zhou, Nahor Haddish-Berhane, Mark Salvati, Sylvie Laquerre, Matthew V. Lorenzi, Dirk Brehmer. JNJ-64619178, a selective and pseudo-irreversible PRMT5 inhibitor with potent in vitro and in vivo activity, demonstrated in several lung cancer models [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 4859.
PRMT5 is a type II methyltransferase that specifically adds methyl groups to arginine as a long-lasting post-translational modification. The PRMT5/MEP50 complex regulates a plethora of cellular processes, such as epigenetics and splicing, which are notable events involved in tumorigenesis. Although not frequently mutated or amplified in tumors, elevated PRMT5 protein levels in lung and hematologic cancers are correlated with poorer survival. The PRMT5 inhibitor JNJ-64619178 has been selected as a clinical candidate based on its high selectivity and potency (subnanomolar range) under different in vitro and cellular conditions, paired with favorable pharmacokinetics and safety properties. JNJ-64619178 binds into the SAM binding pocket and reaches the substrate binding pocket to inhibit PRMT5/MEP50 function in a time-dependent manner. Broad cell line panel profiling of JNJ-64619178 revealed a wide range of sensitivity, which is indicative of a genomic dependency instead of a general cytotoxic on-target consequence of PRMT5 inhibition. Further investigations indicate a synthetic lethal correlation between PRMT5 inhibition and key cancer driver pathways. JNJ-64619178, dosed orally (10 mg/kg, every day), showed selective and efficient blockage of the methylation of SMD1/3 proteins, which are crucial components of the spliceosome and substrates of PRMT5/MEP50. JNJ-64619178 also demonstrated tumor regression in a biomarker-driven human small cell lung cancer xenograft model (NCI-H1048) and prolonged tumor growth inhibition after dosing cessation. In rodent and nonrodent toxicology studies, a tolerated dose of JNJ-64619178 has been identified, with the observed toxicity consistent with on-target activity. In summary, JNJ-64619178 has a favorable preclinical package that supports clinical testing in patients diagnosed with lung cancer and hematologic malignancies. Citation Format: Dirk Brehmer, Tongfei Wu, Geert Mannens, Lijs Beke, Petra Vinken, Dana Gaffney, Weimei Sun, Vineet Pande, Jan-Willem Thuring, Hillary Millar, Italo Poggesi, Ivan Somers, An Boeckx, Marc Parade, Erika van Heerde, Thomas Nys, Carol Yanovich, Barbara Herkert, Tinne Verhulst, Marc Du Jardin, Lieven Meerpoel, Christopher Moy, Gaston Diels, Marcel Viellevoye, Wim Schepens, Alain Poncelet, Joannes T. Linders, Edward C. Lawson, James P. Edwards, Dushen Chetty, Sylvie Laquerre, Matthew V. Lorenzi. A novel PRMT5 inhibitor with potent in vitro and in vivo activity in preclinical lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT02-04. doi:10.1158/1538-7445.AM2017-DDT02-04
The synthesis of cyclopropyl pinacol boronic esters from dibromocyclopropanes via Matteson–Pasto rearrangement is reported. The method is readily scalable and shows limited levels of stereoinduction, with a selectivity that is in part complementary to that observed in existing stereoselective borylcyclopropanation strategies. The method can be used to rapidly access borylcyclopropanes as interesting building blocks for diversely functionalized cyclopropanes.
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