Senthil Kumar Radhakrishnan
Virginia Commonwealth University, VA·Biochemistry
Cells constantly destroy damaged and unneeded proteins in the proteasome, a molecular shredder. Cancer cells, especially in multiple myeloma — a cancer of antibody-producing plasma cells — appear to lean on this machinery more heavily than healthy cells, which is why drugs that block the proteasome are used in the clinic.
- Fields
Biochemistry
Pharmacology
Chemistry
- Topics
protease inhibitor
proteasome
bortezomib resistance
- Grants
- 1 known grant, through Mar 2027
What they work on
- Express and purify DDI2 protease and run high-throughput screens with a protein thermal shift assay, which detects binding by shifts in protein unfolding temperature, to find small molecules that bind DDI2.
- Confirm and prioritize screening hits using orthogonal assays, counter-screens against nonspecific compounds, and biophysical characterization of binding.
- Validate and expand confirmed hits into chemical series, select a chemical probe, and define how the compounds inhibit DDI2.
- Test in cells whether candidate compounds engage DDI2, block activation of the transcription factor NRF1 that restores proteasome gene expression, and drive cancer cells into apoptosis.
More about the research
The catch is that cells fight back. Earlier work from this lab showed that shutting down the proteasome triggers a rescue program: the transcription factor NRF1 turns on genes encoding new proteasome subunits, activity recovers, and the drug loses much of its effect. Preliminary data indicate that removing NRF1 makes proteasome inhibitor therapy work better in a breast cancer xenograft model. The project builds on a specific vulnerability in this rescue loop and aims to find drug-like molecules that exploit it.
Why it matters
Proteasome inhibitors are standard treatment for multiple myeloma, but they rarely keep patients in remission for long, partly because tumor cells rebuild their proteasomes through the DDI2–NRF1 pathway. Chemical inhibitors of the DDI2 protease could make existing proteasome inhibitors more effective, and may have activity on their own, offering a potential route to better and more durable treatment for myeloma and possibly other cancers.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Boaz Tirosh
Case Western Reserve University, OH·Pharmacology
Map the specific defect in mitochondrial respiration that appears when AML cells are treated with the mTORC1 activator AcTor plus a proteasome inhibitor, a drug that blocks protein disposal.
Drew James Adams
Case Western Reserve University, OH·Pharmacology
Determine why small molecules binding the same Cys528 site on Exportin-1 (XPO1), a nuclear transport protein, differ in their effects on nuclear export and cell survival, using structural and functional assays.
Yunsun Nam
University of Texas Southwestern Medical Center, TX·Biochemistry
Determine how heavy metals alter the efficiency and specificity of METTL3-METTL14, the enzyme that adds m6A marks to mRNA, and how metal-driven m6A changes link to chromatin and DNA methylation.
The school
Virginia Commonwealth University: 19 labs on PI Pages, $524M a year on research, 438 research doctorates a year.
Reach out
A start for your email. Fill in the brackets.