IIT Gandhinagar Team Develops Promising Drug Candidate to Combat Resistant Prostate Cancer
Researchers at the Indian Institute of Technology Gandhinagar (IITGN) have developed a new drug molecule that could significantly advance the treatment of prostate cancer, particularly in cases where cancer becomes resistant to standard therapies. The breakthrough centers on a compound called 5n, designed to block a key mechanism that allows cancer cells to survive conventional treatments like androgen deprivation therapy (ADT).
Targeting Cancer’s Repair System
Prostate cancer affects more than 1.4 million men globally every year and is initially manageable through hormone therapy. However, many cases eventually progress into metastatic castration-resistant prostate cancer (mCRPC), a deadly form of the disease that no longer responds to standard treatment. One of the key reasons for this resistance is a cellular repair protein called Tousled-like kinase 1 (TLK1), which helps cancer cells survive by repairing DNA damage caused by therapy.
“Cancer cells activate TLK1 as a survival tactic,” said Dr. Sivapriya Kirubakaran, professor in IITGN’s Department of Chemistry. “When treatments like ADT cause DNA breaks in tumour cells, TLK1 steps in to fix the damage, helping the cancer persist and adapt.”
Improving on Earlier Inhibitors
Historically, TLK1 inhibitors have been based on phenothiazines, a class of antipsychotic drugs. While these compounds do show some inhibition of TLK1, they are not very effective against prostate cancer and often have undesirable side effects.
To overcome these limitations, the IITGN team modified an earlier in-house molecule named J54, which had shown promise against mCRPC. Led by Dr. Delna Johnson, a postdoctoral fellow and the study’s first author, the researchers replaced J54’s core structure and re-engineered it to improve its interaction with TLK1 while reducing toxicity.
The result was a new generation of drug candidates, among which molecule 5n emerged as the most potent.
A Potent Inhibitor With Precision
What sets 5n apart is its non-ATP competitive inhibition. Unlike many drugs that compete with ATP (the cell’s energy currency) to block enzymes, 5n can inhibit TLK1 even when ATP levels are high, making it more effective in living cells.
“By retaining key structural features from J54 and introducing a new amide linker, we created a molecular decoy that selectively disables TLK1 without disrupting other essential cellular functions,” explained Dr. Vijay Thiruvenkatam, associate research professor in IITGN’s Department of Biological Sciences and Engineering.
Promising Results in Lab Tests
When tested on LNCaP cells, a hormone-sensitive prostate cancer cell line, molecule 5n showed remarkable results. Even at low concentrations, it significantly reduced cell survival and hampered the cancer cells’ ability to grow and form new tumors.
The results were even more striking when 5n was combined with Bicalutamide, a widely used anti-androgen drug. The combination therapy caused six-fold greater reduction in cancer cell survival and led to extensive DNA damage, triggering apoptosis — the cancer cell’s self-destruct mechanism.
Moreover, 5n demonstrated low toxicity toward healthy cells, suggesting it can selectively target cancer cells. This is a critical factor in making cancer treatment safer and more tolerable for patients.
The Road Ahead
While 5n is still in the experimental stage, the findings mark a significant step forward in developing targeted therapies for resistant prostate cancer. The IITGN team’s success highlights the growing role of Indian research institutions in cutting-edge cancer drug discovery.
If further pre-clinical and clinical trials support these early results, molecule 5n could eventually form part of a next-generation treatment strategy for prostate cancer patients facing limited options.
AM.
