New research connects tumor metabolism to the selectivity of drugs that target cancer cells. The study examines PRMT5, a protein that regulates gene activity and has been pursued as a drug target for many years. In healthy cells PRMT5 associates with the metabolite SAM, but in tumor cells where MTAP is mutated or deleted it binds MTA instead. This altered interaction occurs in about 10 to 15 percent of cancers and creates a cancer-specific vulnerability.
To measure and quantify drug binding to the MTA-bound PRMT5, the teams used a biosensor strategy built on Promega’s NanoBRET target engagement technology. The University of Oxford team designed CBH-002, a cell-permeable BRET probe that binds a genetically encoded PRMT5‑NanoLuc biosensor and reports drug engagement in live cells. Elizabeth Mira Rothweiler and colleagues showed that CBH-002 can detect different classes of PRMT5 inhibitors and is sensitive to metabolite levels, revealing how MTA alters drug selectivity and why some inhibitors work well in MTAP-deleted cancers.
Ani Michaud and co-authors describe this as the first direct characterization of an uncompetitive inhibitor mechanism in live cells. The authors suggest the results point toward drugs that are active only when PRMT5 is bound to the cancer metabolite MTA, which would limit activity to tumor tissue. The work is a collaboration among Stony Brook University, the University of Oxford, Boston University and the Promega Corporation and received support from the National Institutes of Health.
Difficult words
- metabolite — small molecule produced by cellular processes
- mutate — to change a gene or its sequencemutated
- vulnerability — a weakness that can be targeted medically
- biosensor — device or molecule that detects biological signals
- engagement — binding or interaction between drug and target
- uncompetitive — type of inhibition that needs substrate present
- selectivity — preference of a drug for one target
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Discussion questions
- How might drugs that are active only when PRMT5 binds MTA reduce harm to healthy tissue? Explain with reasons.
- What benefits and challenges could using a biosensor like CBH-002 bring to drug development in live cells?
- Why is the fact that MTAP mutation or deletion occurs in about 10 to 15 percent of cancers important for designing treatments?
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