Reference - Detail
| RRC ID | 69197 |
|---|---|
| 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 |
| 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. |
| Volume | 65(3) |
| Pages | 1749-1766 |
| Published | 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 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 31 |
| Altmetric score changes over past 6months | 8.0 |
| Resource | |
| Human and Animal Cells | Lu99(RCB1900) |