On April 10, 2021 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a late-stage targeted oncology company, reported initial preclinical results evaluating its investigational synthetic lethal PRMT5 inhibitor in methylthioadenosine phosphorylase (MTAP)-deleted cancer models (Press release, Mirati, APR 10, 2021, View Source [SID1234577848]). Mirati’s internally discovered PRMT5 compound is the first to specifically target the PRMT5/methylthioadenosine (MTA) complex. This approach is designed to leverage elevated levels of MTA in cancers exhibiting an MTAP deletion and to selectively kill cancer cells harboring this genetic alteration. The results were presented today during a late-breaking minisymposium at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting [Abstract # LB003].
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Preclinical results showed that the Mirati PRMT5 compound bound selectively to the PRMT5/MTA complex and demonstrated a greater than 100-fold selectivity for MTAP-deleted cells compared with cells that do not exhibit this genetic defect in both proliferation and mechanistic assays. This selectivity for the PRMT5/MTA complex and MTAP-deleted cancer cells allows for the selective targeting of cancer cells while sparing healthy cells, which are also dependent on PRMT5 for cell growth and survival. In addition, treatment of MTAP-deleted tumor xenograft-bearing mice with the Mirati PRMT5 compound resulted in halted tumor growth and near complete reduction of symmetric dimethylarginine (SDMA), a biomarker of PRMT5 activity, at well-tolerated dose levels.
"We are proud to have a potential first-in-class therapeutic agent to specifically target the PRMT5/MTA complex in MTAP-deleted cancer cells," said James Christensen, Ph.D., executive vice president and chief scientific officer, Mirati Therapeutics, Inc. "Based on discoveries made by Mirati scientists, we have designed a novel approach to specifically bind to and inhibit PRMT5 in complex with MTA. With this approach, we are able to target MTAP-deleted tumors, which should result in an improved therapeutic index relative to known PRMT5 and MAT2A inhibitors."
About PRMT5 Inhibition in MTAP-deleted Cancers
PRMT5 is an enzyme critical to the survival of both healthy and cancer cells and is partially inhibited by MTA, which accumulates in MTAP-deleted cancers. The MTAP deletion is present in approximately 10 percent of all cancers and is the most frequently observed gene deletion event (MTAP/CDKN2A) across several cancer types. Cancers with an MTAP deletion, such as pancreatic, lung, and bladder cancers, are associated with a poor prognosis, representing a significant unmet medical need.
Activated PRMT5 is crucial for the regulation of cellular processes essential for cell survival, including regulation of RNA splicing, gene expression and protein translation. In MTAP-deleted cancer cells, the inhibitory cofactor MTA accumulates and binds to PRMT5. Mirati’s PRMT5 compound selectively targets the PRMT5/MTA complex in MTAP-deleted cancer cells while sparing healthy cells. The Mirati PRMT5 compound is advancing toward an Investigational New Drug (IND) filing in the first half of 2022.