GTA182
GTA182 is a MTA-cooperative, brain penetrant, 2nd generation inhibitor of protein arginine methyltransferase 5 (PRMT5)
Protein arginine methyl transferase 5 (PRMT5) is a type II PRMT. It regulates cell growth, development, tissue homeostasis and is essential for cell survival. PRMT5 is broadly expressed in somatic and embryonic tissues.MTAP is co-deleted with the tumor suppressor gene CDKN2A in up to 10% of cancer patients across a broad spectrum of tumor types. Accumulation of MTA in MTAP deleted cells creates synthetic lethal vulnerability to MTA-cooperative PRMT5 inhibitors. GTA182 is an MTA-cooperative PRMT5 inhibitor and consequently demonstrates synthetic lethality in the context of MTAP deletion.
GTA182 is a potent and MTA-cooperative PRMT5i
| Cell proliferation IC50 (nM) | Selectivity (fold) |
|---|---|
| HCT116 MTAPdel | MTAPwt / MTAPdel |
| Less than 20 nM | > 100x |
GTA182 exhibits low double digit nM inhibitory activity in biochemical and cellular assays respectively. It also demonstrates > 100 fold selectivity for MTAP deleted cells compared with MTAP wild-type cells.GTA182 induces tumor regression in MTAPdel xenografts
GTA182 induces sustained tumor regression in a non-small cell lung carcinoma (LU99) MTAP deleted murine xenograft model, with no body weight loss observed up to 60 mg/kg QD dosing. In contrast minimal efficacy is observed in an LU99 MTAP over-expressing (LU99-MTAP-OE) model (data not shown).GTA182 is brain penetrant and induces inhibition of tumor growth in MTAPdel GBM
GTA182 is brain penetrant and induces sustained tumor growth inhibition in an orthotopic glioblastoma (U87) MTAP deleted murine xenograft model, with minimal body weight loss observed.