Nov 1, 2023 · MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells.

Feb 14, 2025 · MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5•MTA complex relative to the PRMT5•SAM complex can lead to selective killing of cancer cells with MTAP deletion.

Fortunately, MTA competes with SAM to generate the PRMT5-MEP50/MTA (PRMT5/MTA) complex in MTAP-deleted tumours. The researchers believe that a small molecule which could bind to and stabilise the PRMT5/MTA complex will selectively inhibit PRMT5 activity in MTAP-deleted tumour cells.

Nov 1, 2023 · These data demonstrate that MRTX1719 selectively binds to the PRMT5/MEP50/MTA complex and exhibits increased potency against PRMT5 in the presence of MTA. In addition, MRTX1719 was evaluated in a biochemical assay format amenable to testing whether an inhibitor is peptide substrate competitive.

Mar 4, 2025 · Targeting MTAP-null cancer cells via selective inhibition of the PRMT5·MTA complex can improve tolerability relative to nonselective PRMT5 inhibitors (8−11) by limiting inhibition of PRMT5 in normal cells.

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.

Sep 2, 2024 · MTA exhibited a significantly stronger binding affinity to the PRMT5/MEP50 complex than SAM. These findings are crucial for understanding the role of MTA in the inhibition of PRMT5, particularly in cancer cells with MTAP deletions, where MTA accumulates and competes with SAM.

Nov 4, 2021 · 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.

Apr 4, 2023 · In MTAP del cells, MTA accumulates and partially inhibits PRMT5 activity by directly competing with SAM, the universal methyl donor and PRMT5 substrate. Thus, the deletion of MTAP leads to the formation of the PRMT5-MTA complex …

MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5•MTA complex relative to the PRMT5•SAM complex can lead to selective killing of cancer cells with MTAP deletion.