Reference - Detail
|Author||Smith CR, Aranda R, Bobinski TP, Briere DM, Burns AC, Christensen JG, Clarine J, Engstrom LD, Gunn RJ, Ivetac A, Jean-Baptiste R, Ketcham JM, Kobayashi M, Kuehler J, Kulyk S, Lawson JD, Moya K, Olson P, Rahbaek L, Thomas NC, Wang X, Waters LM, Marx MA.|
|Title||Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers.|
|Journal||J Med Chem|
The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP-deleted cancers. Here, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in MTAP-deleted cells compared to MTAP-wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP-deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2H)-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719.
|MeSH||Animals Antineoplastic Agents / chemical synthesis Antineoplastic Agents / metabolism Antineoplastic Agents / therapeutic use* Cell Line, Tumor Deoxyadenosines / metabolism Female Gene Deletion Humans Mice, Nude Neoplasms / drug therapy* Phthalazines / chemical synthesis Phthalazines / metabolism Phthalazines / therapeutic use* Protein Binding Protein-Arginine N-Methyltransferases / antagonists & inhibitors* Protein-Arginine N-Methyltransferases / metabolism Purine-Nucleoside Phosphorylase / deficiency Purine-Nucleoside Phosphorylase / genetics Thionucleosides / metabolism Xenograft Model Antitumor Assays|
|Human and Animal Cells||Lu99(RCB1900)|