論文 - 詳細
| RRC ID | 69197 |
|---|---|
| 著者 | 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. |
| タイトル | Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers. |
| ジャーナル | J Med Chem |
| Abstract |
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. |
| 巻・号 | 65(3) |
| ページ | 1749-1766 |
| 公開日 | 2022-2-10 |
| DOI | 10.1021/acs.jmedchem.1c01900 |
| PMID | 35041419 |
| 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 |
| IF | 6.205 |
| リソース情報 | |
| ヒト・動物細胞 | Lu99(RCB1900) |